Articles de revues : « Anti-PSMA antibody »

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Mizutani, Kosuke, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie et Masafumi Ito. « Abstract 5332 : Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5332. http://dx.doi.org/10.1158/1538-7445.am2022-5332.

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Abstract Perforin secreted from cytotoxic T cells and natural killer cells play important roles in anti-tumor immunoreaction leading to cancer cell apoptosis. The aim of this study is to investigate whether perforin-rich tumor microenvironment could inhibit tumor growth. Advanced prostate cancer (PC) expresses high amount of prostate-specific antigen (PSA) that is a possible therapeutic target, therefore, we constructed a PSA promoter-driven perforin expression vector for its predominant expression in tumor microenvironment of PC. Prostate membrane-specific antigen (PSMA) expressed on PC cell surface is also an attractive therapeutic target. To deliver perforin expression vector to PC, it was encapsulated in liposomes conjugated with anti-PSMA antibody (PSMA-pLipo), then the anti-tumor effect of PSMA-pLipo was evaluated using docetaxel-resistant PC cell line, 22Rv1DR, expressing both PSA and PSMA. The conjugated anti-PSMA antibody on PSMA-pLipo recognized recombinant PSMA protein, and incubation with PSMA-pLipo induced perforin expression in 22Rv1DR cells but not in PC-3 cells not expressing both PSA and PSMA. Growth of 22Rv1DR and PC-3 cells was barely inhibited by PSMA-pLipo alone. Perforin functions in concert with cytotoxic lymphocytes, therefore anti-tumor effect of PSMA-pLipo was analyzed in the presence of human peripheral blood mononuclear cells (PBMCs). Low concentration of PSMA-pLipo with human PBMCs significantly inhibited growth of 22Rv1DR cells but not PC-3 cells. High concentration of PSMA-pLipo with human PBMCs showed nearly complete inhibition of 22Rv1DR cell growth. In a mouse xenograft model implanted with 22Rv1DR cells, PSMA-pLipo was intravenously administrated via tale vein and tumor volume was monitored. PSMA-pLipo inhibited growth of 22Rv1DR cells compared to injection of anti-PSMA antibody alone. The data presented here suggest that gene therapy expressing perforin specifically in PC cells could be a novel therapy for advanced PC. Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie, Masafumi Ito. Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5332.

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Akhtar, Naveed H., Orrin Pail, Ankeeta Saran, Lauren Tyrell et Scott T. Tagawa. « Prostate-Specific Membrane Antigen-Based Therapeutics ». Advances in Urology 2012 (2012) : 1–9. http://dx.doi.org/10.1155/2012/973820.

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Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with177Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials.

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Milowsky, Matthew I., David M. Nanus, Lale Kostakoglu, Christine E. Sheehan, Shankar Vallabhajosula, Stanley J. Goldsmith, Jeffrey S. Ross et Neil H. Bander. « Vascular Targeted Therapy With Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Advanced Solid Tumors ». Journal of Clinical Oncology 25, n^o 5 (10 février 2007) : 540–47. http://dx.doi.org/10.1200/jco.2006.07.8097.

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Purpose Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response. Patients and Methods Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues. Results Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment. Conclusion Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

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Buelow, Ben, Starlynn Clarke, Kevin Dang, Jacky Li, Chiara Rancan, Yuping Li, Preethi Sankaran et al. « Evaluation of monovalent versus biparatopic CD3xPSMA bispecific antibodies for t-cell mediated killing of prostate tumor cells with minimal cytokine release. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : e16519-e16519. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16519.

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e16519 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new treatments are needed. Therapies directed against Prostate specific membrane antigen (PSMA) -such as radiolabeled antibodies, chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs)- have shown promising efficacy but also induce significant toxicity. In particular T-cell redirection leads to efficient killing of tumor cells but induces cytokine release-related toxicities. We have developed a panel of monovalent and biparatopic CD3xPSMA bispecific antibodies that eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats (UniRat™, OmniFlic™) followed by deep sequencing of the antibody repertoire from draining lymph nodes in immunized animals, and high-throughput gene assembly/expression. PSMA x CD3 T-BsAbs were assembled and evaluated for stability, pharmacokinetics, and T cell activation and ability to eliminate PSMA+ tumor cells in vitro and in vivo. Results: Bispecific CD3xPSMA Abs. incorporating either monovalent or biparatopic anti-PSMA binding domains activated T-cells in the presence of PSMA (plate-bound or cell surface), while no T cell activation occurred in the absence of either PSMA antigen or bispecific antibody. Potent/selective cytotoxicity against PSMA+ cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA T-BsAbs. Similar results were observed in in vivo Xenograft models of prostate cancer. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cytotoxicity compared to those with a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies incorporating both monovalent and biparatopic anti-PSMA binding domains that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.

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Xing, Yutong, Keyuan Xu, Shixiong Li, Li Cao, Yue Nan, Qiyu Li, Wenjing Li et Zhangyong Hong. « A Single-Domain Antibody-Based Anti-PSMA Recombinant Immunotoxin Exhibits Specificity and Efficacy for Prostate Cancer Therapy ». International Journal of Molecular Sciences 22, n^o 11 (23 mai 2021) : 5501. http://dx.doi.org/10.3390/ijms22115501.

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Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.

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Wang, Xinning, Aditi Shirke, Ethan Walker, Rongcan Sun, Gopolakrishnan Ramamurthy, Jing Wang, Lingpeng Shan et al. « Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer ». Cancers 13, n^o 3 (22 janvier 2021) : 417. http://dx.doi.org/10.3390/cancers13030417.

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Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.

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Magargal, Wells Wrisley, Dapeng Qian et William C. Olson. « Expression of prostate-specific membrane antigen (PSMA) in the neovasculature of nonprostate human tumors of epithelial and nonepithelial origin. » Journal of Clinical Oncology 30, n^o 15_suppl (20 mai 2012) : e21131-e21131. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21131.

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e21131 Background: PSMA is a transmembrane glycoprotein present not only in prostate cancer epithelial cells but also in the neovasculature of many other solid tumors. This expression profile makes it an attractive target for tumor-specific delivery of chemotherapeutic agents to the neovasculature of non-prostate solid tumors. We generated an antibody-drug conjugate (ADC) comprised of a fully human anti-PSMA monoclonal antibody (mAb), conjugated to monomethylauristatin E, a potent cytotoxic agent. PSMA ADC is currently undergoing Phase I clinical testing in men with advanced prostate cancer. Previously, we reported high level PSMA expression in the neovasculature of carcinomas from kidney, colon, non-small cell lung, breast and liver. Here we extend our study to additional carcinomas as well as tumors of non-epithelial origin. Methods: Expression of PSMA protein was evaluated by immunohistochemical analysis of frozen tissues using biotinylated mAb that specifically recognizes the native dimeric form of PSMA. The semi-quantitative scheme of 0 to 3+ was used to indicate the amount of epitope based on the intensity of the color reaction. The strongest possible staining was scored 3+ while 2+ staining was considered moderate and 1+ was considered weak. Endothelial cells were detected by morphology and staining of selected slides with an anti-CD 34 mAb. Results: Moderate to strong (2+ to 3+) neovasculature staining was seen in over 80% of specimens from, bladder (10/10), ovarian (9/10) and pancreatic (8/10) carcinomas. Moderate to strong neovascular staining was seen in 40-80% of specimens from several non-carcinoma tumors, including glioblastoma (4/5), melanoma (7/10), non-Hodgkins lymphoma (6/10), osteosarcoma (3/7) and myeloma (2/5). Only weak (1+) staining was seen in angiosarcoma (2/3) and no staining was observed in the testicular cancers tested (0/5). Conclusions: Robust neovascular expression of PSMA dimer was observed across all eight non-prostatic carcinomas. Significant neovascular expression was also observed in several non-epithelial tumors. These findings may be relevant to the development of novel anti-neovascular therapies that target PSMA.

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Clarke, Starlynn, Kevin Dang, Yuping Li, Preethi Sankaran, Duy Pham, Aarti Balasubramani, Laura Davison et al. « A novel CD3xPSMA bispecific antibody for efficient T cell mediated killing of prostate tumor cells with minimal cytokine release. » Journal of Clinical Oncology 37, n^o 7_suppl (1 mars 2019) : 324. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.324.

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324 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs potently kill tumor cells but induce cytokine release-related toxicities. Novel anti-CD3 engaging domains may be required to create T-BsAbs with a broader therapeutic window. We have developed fully human CD3xPSMA bispecific antibodies that efficiently eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats that produce human antibodies (UniRat, OmniFlic) followed by repertoire deep sequencing of lymph nodes isolated from immunized animals and high-throughput gene assembly/expression. CD3xPSMA T-BsAbs were assembled and evaluated for T cell activation and ability to eliminate PSMA+ tumor cells in vitro. Results: Primary human T cells were activated only in the presence of both bispecific CD3xPSMA antibodies and PSMA (either plate-bound or on the surface of tumor cells). Potent and selective cytotoxicity against PSMA+ prostate tumor cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA bispecific antibodies. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cell cytotoxicity compared to CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.

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Dang, Kevin, Giulia Castello, Starlynn C. Clarke, Yuping Li, Aarti Balasubramani, Andrew Boudreau, Laura Davison et al. « Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release ». Journal for ImmunoTherapy of Cancer 9, n^o 6 (juin 2021) : e002488. http://dx.doi.org/10.1136/jitc-2021-002488.

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BackgroundTherapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3.MethodsUsing genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice.ResultsIn vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo.ConclusionsOur data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.

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Buelow, Ben, Kevin Dang, Pranjali Dalvi, Yuping Li, Alexander Cheung, Chiara Rancan, Preethi Sankaran et al. « Effect of modulation of CD3 binding in a PSMAxCD3 T-cell engaging bispecific antibody on maintenance of efficient tumor cell kill and cytokine release. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : e17583-e17583. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17583.

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e17583 Background: Castration resistant prostate cancer (CRPC) is an incurable disease and represents a significant unmet need. Prostate specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells; expression has been shown to increase with disease progression. Therapies targeting PSMA, such as anti-PSMA radioligand conjugates, have shown promise in clinical trials, validating this target for CRPC. T-cell recruiting bispecific antibodies (T-BsAbs) have demonstrated potent tumor killing activity against multiple tumor types, but immune-mediated toxicities have hampered T-cell redirecting therapies to date. Using Teneobio’s unique antibody discovery platform, we have developed a CD3xPSMA bispecific antibody (TNB-585) that retains the potent cytotoxicity of other T-BsAbs but with significantly reduced cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated via immunization of our proprietary transgenic animals. Candidate antibodies were selected by repertoire deep sequencing of B-cells from draining lymph nodes, followed by high-throughput gene assembly and recombinant expression. Multiple bispecific antibodies targeting CD3 and PSMA were assembled and evaluated for their ability to selectively activate primary human T-cells and mediate killing of PSMA+ tumor cells in vitro, ex vivo, and in vivo. T-cell activation surface markers, cytokine production, and tumor cell cytotoxicity were measured. Results: In co-culture experiments, primary human T-cells were activated only in the presence of both the bispecifics and PSMA+ cells. These bispecifics mediated potent and selective cytotoxicity against PSMA-positive tumor cells, prostate tumor cell lines, or primary human prostate tumor cells isolated from patients. From among these we identified TNB-585, which showed attenuated binding to CD3. TNB-585 mediated comparable tumor cell cytotoxicity to CD3xPSMA T-BsAbs containing a high affinity anti-CD3 domain but with significantly reduced cytokine production. TNB-585 also showed tumor growth inhibition in xenograft models of prostate cancer in vivo. Conclusions: We have developed a novel CD3xPSMA T-BsAb that mediates T-cell killing of PSMA+ tumor cells with minimal production of cytokines. This molecule may improve safety, efficacy, and offer opportunities for combination therapy to treat CRPC. A Phase 1 clinical trial of this compound in CRPC is scheduled to begin in Q1 2021.

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Petrylak, Daniel Peter, Philip W. Kantoff, Anthony E. Mega, Nicholas J. Vogelzang, Joe Stephenson, Mark T. Fleming, Nancy Stambler, Michaela Petrini, Sara Blattman et Robert Joseph Israel. « Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) : A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. » Journal of Clinical Oncology 31, n^o 15_suppl (20 mai 2013) : 5018. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5018.

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5018 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized within the cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. A phase 1 dose escalation study of PSMA ADC in taxane-refractory mCRPC has been completed. Methods: Patients with progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1 were eligible. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics, PSA, circulating tumor cells (CTC), immunogenicity and clinical progression were assessed. Serum PSMA ADC and total anti-PSMA ADC antibodies were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Subjects who benefitted from PSMA ADC were eligible for treatment in an extension study. Results: 52 subjects were dosed in 9 dose levels. All subjects received prior docetaxel, 6 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. 16 patients reported peripheral neuropathies, including 3 with grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible elevations in liver function tests (LFTs). Antitumor activity was manifested as reductions either in PSA or in CTCs in approximately 50% of patients at ≥ 1.8 mg/kg PSMA ADC. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. There was no accumulation. Conclusion: PSMA ADC in this study was generally well tolerated in subjects with progressive mCRPC, previously treated with taxane. Antitumor activity was seen at doses ≥ 1.8 mg/kg. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose was determined to be 2.5 mg/kg. A phase 2 trial of PSMA ADC in taxane refractory mCRPC has been initiated at 2.5 mg/kg. Clinical trial information: NCT01414283.

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Schol, D., M. Fleron, J. F. Greisch, M. Jaeger, M. Frenz, E. De Pauw et M. C. De Pauw-Gillet. « Anti-PSMA antibody-coupled gold nanorods detection by optical and electron microscopies ». Micron 50 (juillet 2013) : 68–74. http://dx.doi.org/10.1016/j.micron.2013.05.003.

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Stopa, Brittany M., James Crowley, Csaba Juhász, Cara M. Rogers, Mark R. Witcher et Jackson W. Kiser. « Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors ». Molecular Imaging 2022 (15 avril 2022) : 1–23. http://dx.doi.org/10.1155/2022/5358545.

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Introduction. Positron emission tomography (PET) imaging with prostate-specific membrane antigen- (PSMA-) binding tracers has been found incidentally to demonstrate uptake in CNS tumors. Following the encouraging findings of several such case reports, there is a growing interest in the potential application of PSMA-targeted PET imaging for diagnostics, theranostics, and monitoring of CNS tumors. This is a systematic literature review on PSMA-binding tracers in CNS tumors. Methods. A PubMed search was conducted, including preclinical and clinical reports. One hundred and twelve records were identified, and after screening, 56 were included in the final report. Results. Tissue studies demonstrated PSMA expression in tumor vascular endothelial cells, without expression in normal brain tissue, though the extent and intensity of staining varied by anti-PSMA antibody and methodology. Most included studies reported on gliomas, which showed strong PSMA ligand uptake and more favorable tumor to background ratios than other PET tracers. There are also case reports demonstrating PSMA ligand uptake in prostate cancer brain metastases, nonprostate cancer brain metastases, and meningiomas. We also review the properties of the various PSMA-binding radiotracers available. Therapeutic and theranostic applications of PSMA-binding tracers have been studied, including labeled alpha- and beta-ray emitting isotopes, as well as PSMA targeting in directing MRI-guided focused ultrasound. Conclusions. There is a potential application for PSMA-targeted PET in neuro-oncology as a combination of diagnostic and therapeutic use, as a theranostic modality for managing CNS tumors. Further research is needed regarding the mechanism(s) of PSMA expression in CNS tumors and its differential performance by tumor type.

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Zare, Hamed, Masoumeh Rajabibazl, Iraj Rasooli, Walead Ebrahimizadeh, Hamid Bakherad, Leila Safaiee Ardakani et Seyed Latif Mousavi Gargari. « Production of Nanobodies against Prostate-Specific Membrane Antigen (PSMA) Recognizing LnCaP Cells ». International Journal of Biological Markers 29, n^o 2 (avril 2014) : 169–79. http://dx.doi.org/10.5301/jbm.5000063.

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Prostate cancer is the most common type of cancer in men. The antibody-mediated therapy for cancer treatment depends on the identification of selected molecular targets. The prostate-specific membrane antigen (PSMA) is a potential molecular target in prostate cancer and is abundantly expressed in this type of cancer. This study is aimed at designing and producing a recombinant PSMA epitope and a monoclonal nanobody with a high affinity toward the PSMA protein. A DNA fragment encoding the dominant epitopes of PSMA was designed, synthesized, and expressed in E. coli BL21 (DE3). A camel was immunized with the purified recombinant PSMA (rPSMA). Following mRNA isolation and cDNA synthesis, the variable fragment of heavy-chain antibodies (VHH) fragments were cloned and displayed on the surface of an M13 phage and used in sequential panning rounds. After phage ELISA and selection of colonies with the highest affinity, soluble nanobodies were produced and evaluated. Affinity of the nanobodies to rPSMA was estimated to be 3.5 × 10−7. Adherence of the purified anti-PSMA VHH was tested in cell-ELISA in the LnCaP and PC3 cell lines. VHH efficiently bound to LnCaP cells. The high specificity and affinity of this nanobody suggests its possible application as an effective tool in the diagnosis and treatment of prostate cancer.

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Serda, Rita E., Natalie L. Adolphi, Marco Bisoffi et Laurel O. Sillerud. « Targeting and Cellular Trafficking of Magnetic Nanoparticles for Prostate Cancer Imaging ». Molecular Imaging 6, n^o 4 (1 juillet 2007) : 7290.2007.00025. http://dx.doi.org/10.2310/7290.2007.00025.

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Antibody-conjugated iron oxide nanoparticles offer a specific and sensitive tool to enhance magnetic resonance (MR) images of both local and metastatic cancer. Prostate-specific membrane antigen (PSMA) is predominantly expressed on the neovasculature of solid tumors and on the surface of prostate cells, with enhanced expression following androgen deprivation therapy. Biotinylated anti-PSMA antibody was conjugated to streptavidin-labeled iron oxide nanoparticles and used in MR imaging and confocal laser scanning microscopic imaging studies using LNCaP prostate cancer cells. Labeled iron oxide nanoparticles are internalized by receptor-mediated endocytosis, which involves the formation of clathrin-coated vesicles. Endocytosed particles are not targeted to the Golgi apparatus for recycling but instead accumulate within lysosomes. In T1-weighted MR images, the signal enhancement owing to the magnetic particles was greater for cells with magnetic particles bound to the cell surface than for cells that internalized the particles. However, the location of the particles (surface vs internal) did not significantly alter their effect on T2-weighted images. Our findings indicate that targeting prostate cancer cells using PSMA offers a specific and sensitive technique for enhancing MR images.

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Comparetti, Edson José, Graziela Gorete Romagnoli, Carolina Mendonça Gorgulho, Valber de Albuquerque Pedrosa et Ramon Kaneno. « Anti-PSMA monoclonal antibody increases the toxicity of paclitaxel carried by carbon nanotubes ». Materials Science and Engineering : C 116 (novembre 2020) : 111254. http://dx.doi.org/10.1016/j.msec.2020.111254.

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Czerwińska, Malwina, Giulio Fracasso, Marek Pruszyński, Aleksander Bilewicz, Marcin Kruszewski, Agnieszka Majkowska-Pilip et Anna Lankoff. « Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy–Part I ». Materials 13, n^o 17 (2 septembre 2020) : 3875. http://dx.doi.org/10.3390/ma13173875.

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Prostate cancer is the second most frequent malignancy in men worldwide. Unfortunately, current therapies often lead to the onset of metastatic castration-resistant prostate cancer (mCRPC), causing significant mortality. Therefore, there is an urgent need for new and targeted therapies that are advantageous over the current ones. Recently, the PSMA-targeted radioligand therapy of mCRPC has shown very promising results. In line with this, we described the synthesis of a new radioimmunoconjugate, 223RaA-silane-PEG-D2B, for targeted mCRPC therapy. The new compound consists of a NaA zeolite nanocarrier loaded with the α-particle emitting Ra-223 radionuclide, functionalized with the anti-PSMA D2B antibody. Physicochemical properties of the synthesized compound were characterized by standard methods (HR-SEM, TEM, XRD, FTIR, EDS, NTA, DLS, BET, TGA). The targeting selectivity, the extent of internalization, and cytotoxicity were determined in LNCaP C4-2 (PSMA+) and DU-145 (PSMA-) cells. Our results supported the 223RaA-silane-PEG-D2B synthesis and revealed that the final product had a diameter ca. 120 nm and specific activity 0.65 MBq/1mg. The product was characterized by a high yield of stability (>95% up to 12 days). The conjugation reaction resulted in approximately 50 antibodies/nanoparticle. The obtained radioimmunoconjugate bound specifically and internalized into PSMA-expressing LNCaP C4-2 cells, but not into PSMA-negative DU-145 cells. 223RaA-silane-PEG-D2B demonstrated also potent cytotoxicity in LNCaP C4-2 cells. These promising results require further in vivo evaluation of 223RaA-silane-PEG-D2B with regard to its toxicity and therapeutic efficacy.

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Stangl-Kremser, Judith, Sazan Rasul, Jeffrey J. Tosoian, Simpa Salami, Alexander Zaslavsky, Aaron M. Udager, Peter Mazal et al. « Single-lesion PSMA protein expression and response to Lu-177 PSMA therapy in patients with castration-resistant prostate cancer. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 5065. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5065.

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5065 Background: The recent introduction of Lu-177 PSMA for the treatment of castration-resistant prostate cancer (CRPC) has been met with much excitement. Initial reports of clinical response are promising, despite known inter- and intra-patient molecular heterogeneity. In this study, we examined the utility of PSMA protein expression in metastatic tumor tissues as a predictor of lesion-specific response to Lu-177 PSMA therapy in men with CRPC. Methods: Between 2015-2020, 19 patients with metastases at multiple sites underwent metastatic lesion biopsy, Ga-68 PSMA PET imaging, and subsequent treatment with three cycles of Lu-177 PSMA. A monoclonal anti-PSMA antibody (EPITOMICS (USA), 1:50) was used to semi-quantitatively assess PSMA protein expression in the biopsy specimen. The histoscore (range 0-300) was derived from intensity and extent of the immunohistochemistry staining and was determined by experienced genitourinary pathologists. Imaging evaluation was performed according to the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. We assessed the association of the PSMA protein expression in metastatic tumor tissues and the lesion-specific response to Lu-177 PSMA therapy. Results: In 12 patients with biopsy specimens available for staining, PSMA expression correlated with enhancement (SUVmax) of the biopsy site on Ga-68 PSMA PET imaging (rs = 0.63). Of the nine patients with repeat imaging after Lu-177 PSMA therapy, five (55.6%) had a lesion-specific response at the site of biopsy. PSMA expression on immunohistochemistry was unable to accurately predict lesion-specific response in univariable analysis (p = 0.81, 95% CI 94.6-76.6). Among the five men with a lesion-specific response, three (60%) experienced overall progression based on PERCIST. There was no association between lesion-specific response and overall progression (p = 0.64). Conclusions: In patients with multiple metastases, PSMA protein expression from a single site biopsy was not predictive of site-specific Lu-177 PSMA response based on PERCIST. Additional studies are necessary to further interrogate the clinical consequence of PSMA expression heterogeneity in metastatic sites as well as the mechanisms underpinning resistance to Lu-177 PSMA in patients with CRPC.

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Al-Buheissi, S., M. Ghei, P. Hunter-Campbell, N. Khan, K. Chester et A. Maraj B. Markham. « 724The expression of prostate-specific membrane antigen (PSMA) in human tissues using a novel highly specific polycolonal anti-PSMA antibody ». European Urology Supplements 4, n^o 3 (mars 2005) : 183. http://dx.doi.org/10.1016/s1569-9056(05)80728-6.

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Petrylak, Daniel Peter, David C. Smith, Leonard Joseph Appleman, Mark T. Fleming, Arif Hussain, Robert Dreicer, A. Oliver Sartor et al. « A phase II trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 32, n^o 4_suppl (1 février 2014) : 83. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.83.

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83 Background: The abundant expression of prostate-specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA antibody drug conjugate (ADC) is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized and cleaved by lysosomal enzymes releasing free MMAE causing cell cycle arrest and apoptosis. We enrolled 70 patients (pts) in a phase II trial of PSMA ADC in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). Methods: Pts with progressive mCRPC following taxane and ECOG PS 0 or 1 were eligible. PSMA ADC was administered Q3 week IV for up to eight cycles. Safety, tumor response by prostate-specific antigen (PSA), circulating tumor cells (CTC), imaging, biomarkers and clinical progression were assessed. Dosing was initiated at 2.5 mg/kg and adjustment for tolerability was allowed. Results: Thirty five pts began treatment at 2.5 mg/kg. Due to neutropenia, the remaining 35 pts began at 2.3 mg/kg. All pts received prior docetaxel and abiraterone and/or enzalutamide. Forty one percent also received cabazitaxel. Adverse events (AEs) were consistent with what was seen in phase I; most common significant AEs were neutropenia (grade 4, 6.7% and 11.4% at 2.3 and 2.5 mg/kg, respectively) and peripheral neuropathy (grade 3 or higher, 6.7% (2.3) and 5.7% (2.5)). Two pts at 2.5 mg/kg died of sepsis. 43% of pts at 2.3 and 37% of pts at 2.5 had declines in CTC from 5 or more to less than 5 cells/7.5 ml blood and 57.1% (2.3) and 74.1% (2.5) had 50% or more CTC declines; 26.1% (2.3) and 16.1% (2.5) had PSA declines of 30% or more thus far. PSA and CTC responses were associated with higher PSMA expression on CTC and lower neuroendocrine (NE) markers. The CTC conversion rate (5 or more to less than 5) was approximately 80% in pts with low NE markers. Prior cabazitaxel or abiraterone and/or enzalutamide did not appear to affect response. Centralized assessments of images by RECIST of all pts are currently planned and will be presented. Conclusions: PSMA ADC at 2.3 mg/kg was generally well tolerated in pts with progressive mCRPC previously treated with taxane. Anti-tumor activity, CTC and PSA reductions were observed at 2.3 and 2.5 mg/kg. Updated safety, tumor response and radiographic assessments from the full cohorts of 2.3 and 2.5 mg/kg will be presented. Testing in taxane naïve pts is also ongoing. Clinical trial information: NCT01695044.

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Pachynski, Russell K., Luke Nordquist, Michael T. Schweizer, John Shen, Nabil Adra, Mehmet A. Bilen, Zachery R. Reichert et al. « Abstract CT211 : A phase 1 dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, and anti- tumor activity of ARX517 in subjects with advanced solid tumors resistant or refractory to standard therapies (APEX-01 trial, NCT04662580) ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : CT211. http://dx.doi.org/10.1158/1538-7445.am2022-ct211.

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Abstract Background: Novel anti-PSMA (prostate-specific membrane antigen) targeted therapies have exhibited encouraging antitumor activity in prostate cancer and most non-prostate solid tumors express PSMA in tumor neovasculature. ARX517 is an antibody drug conjugate composed of a fully humanized anti-PSMA monoclonal antibody linked to pAF-AS269, a potent microtubule inhibitor. Upon binding to PSMA on the surface of cancer cells, ARX517 is internalized and pAF-AS269 is released following lysosomal metabolism. Methods: This Phase 1, dose-escalation and dose-expansion study is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in adults with prostate cancer or other solid tumors whose disease is resistant or refractory to standard therapies. Patients must have metastatic castration-resistant prostate cancer refractory to standard therapies, including abiraterone, darolutamide, apalutamide or enzalutamide and progression by Prostate Cancer Working Group criteria. Non-prostate advanced solid tumors must be pathologically confirmed, metastatic, or unresectable solid tumors that have disease progression despite at least 1 prior standard of care systemic treatment and have no satisfactory treatment alternatives. All patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability. Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging, which is optional for low dose cohorts but required starting at 1.4 mg/kg dose. Dose-escalation will consist of ascending dose levels of ARX517 administered as a single agent and will use a i3+3 design. The number of subjects in the dose-expansion will be based on the number of doses to be expanded for further evaluation of safety, PK, and clinical activity. Through dose levels one and two, no dose limiting toxicities have been observed. Ascending dose levels of ARX517 as a single agent will be administered until the recommended Phase 2 dose or maximum tolerated dose is determined. Status: ARX517-2011 began recruiting patients in July 2021 and as of January 2022 has completed enrollment in the 3rd cohort of dose-escalation. Citation Format: Russell K. Pachynski, Luke Nordquist, Michael T. Schweizer, John Shen, Nabil Adra, Mehmet A. Bilen, Zachery R. Reichert, Rahul Aggarwal, Bilal A. Siddiqui, Matt Li, Dong Xu, Richard Huhn, Darryl Z. L'Heureux, Jinchun Yan, Ying Buechler, Sulan Yao, John Simitzi, Wenge Shi, Shawn Zhang, Scott T. Tagawa. A phase 1 dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, and anti- tumor activity of ARX517 in subjects with advanced solid tumors resistant or refractory to standard therapies (APEX-01 trial, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT211.

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Wiehr, Stefan, Patrick Bühler, Dorothee Gierschner, Philipp Wolf, Anna-Maria Rolle, Christian Kesenheimer, Bernd J. Pichler et Ursula Elsässer-Beile. « Pharmacokinetics and PET imaging properties of two recombinant anti-PSMA antibody fragments in comparison to their parental antibody ». Prostate 74, n^o 7 (9 mars 2014) : 743–55. http://dx.doi.org/10.1002/pros.22794.

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Frigerio, Barbara, Elena Luison, Alessandro Desideri, Federico Iacovelli, Chiara Camisaschi, Ettore C. Seregni, Silvana Canevari et Mariangela Figini. « Validity of Anti-PSMA ScFvD2B as a Theranostic Tool : A Narrative-Focused Review ». Biomedicines 9, n^o 12 (10 décembre 2021) : 1870. http://dx.doi.org/10.3390/biomedicines9121870.

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Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for 123I(SPECT), 124I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.

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Tagawa, S. T., D. Scherr, J. Batra, Y. Jhanwar, B. Robinson, D. Nanus, H. Beltran, A. Molina, P. Christos et N. Bander. « Anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 immunotherapy for prostate cancer ». Annals of Oncology 27 (octobre 2016) : vi265. http://dx.doi.org/10.1093/annonc/mdw372.55.

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Leconet, Wilhem, He Liu, Ming Guo, Sophie Le Lamer-Déchamps, Charlotte Molinier, Sae Kim, Tjasa Vrlinic et al. « Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation ». Molecular Cancer Therapeutics 17, n^o 9 (11 juin 2018) : 1927–40. http://dx.doi.org/10.1158/1535-7163.mct-17-1138.

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Kelly, William Kevin, Pradeep Thanigaimani, Furong Sun, Frank A. Seebach, Israel Lowy, Sabina Sandigursky et Elizabeth Miller. « A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : TPS5105. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.tps5105.

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TPS5105 Background: Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in American men. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA) is highly expressed on malignant prostate tissue but shows limited expression on normal tissue. As such, PSMA is an excellent research target for treatment of mCRPC. REGN4336 is a PSMAxCD3 bispecific antibody designed to facilitate T-cell–mediated killing of PSMA-expressing tumor cells. In preclinical models, REGN4336 demonstrated strong PSMA-dependent antitumor activity that was dose-dependent. Preclinical data also support clinical research into the combination of REGN4336 with cemiplimab (anti–programmed cell death-1) for treating mCRPC. Methods: This is an open-label, Phase 1/2, first-in-human, multicenter dose-escalation study with dose expansion evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of REGN4336 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with mCRPC (NCT05125016). Patients must have received at least two prior lines of systemic therapy approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. In this study, REGN4336 as monotherapy is administered weekly but may be extended to once every 3 weeks following identification of the minimal pharmacologically active dose. REGN4336 in combination with cemiplimab (350 mg) will be administered once every 3 weeks after a 4-week REGN4336 monotherapy lead-in cycle. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of REGN4336 alone and in-combination with cemiplimab. Expansion cohort(s) will be enrolled once RP2DRs have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate with REGN4336 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. This study is currently open to enrollment. Clinical trial information: NCT03088540.

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Tagawa, Scott T., Shankar Vallabhajosula, Jaspreet Batra, Paul J. Christos, Yuliya Jhanwar, Stanley J. Goldsmith, David M. Nanus et al. « Phase I dose-escalation study of fractionated-dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : TPS5093. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps5093.

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TPS5093 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of radiolabeled anti-PSMA antibody J591 revealed 1) targeting and safety [Bander 2003]; 2) safety and prelim efficacy [Milowsky 2004, Bander 2005]; 3) efficacy and initial dose-response [Tagawa 2013]; 4) dose-fractionation allows higher doses, ability to combine with docetaxel, confirmation of dose-response (PSA and overall survival) [ASCO 2010, 2014, 2016]; 5) predictable, reversible myelosuppression is dose-limiting [Tagawa 2013]. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and are widely used for imaging and treatment in Europe. 177Lu-PSMA-617 is the most commonly used, but experience is mostly anecdotal/retrospective and no formal dose-escalation studies have been performed. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function will undergo imaging with 68Ga-PSMA-HBED-CC PET/CT followed by escalating fractionated doses of 177Lu-PSMA-617. Cohort 1 = 3.7 GBq x2 two weeks apart up to 11.1 GBq x2 in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu-PSMA-617, CTC count (CellSearch) changes, tissue and circulating genomic assessment of DNA repair pathways, patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03042468.

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Lütje, Susanne, Danny Gerrits, Janneke D. Molkenboer-Kuenen, Ken Herrmann, Giulio Fracasso, Marco Colombatti, Otto C. Boerman et Sandra Heskamp. « Characterization of Site-Specifically Conjugated Monomethyl Auristatin E– and Duocarmycin-Based Anti-PSMA Antibody–Drug Conjugates for Treatment of PSMA-Expressing Tumors ». Journal of Nuclear Medicine 59, n^o 3 (16 novembre 2017) : 494–501. http://dx.doi.org/10.2967/jnumed.117.196279.

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Liu, Jihua, Pavla Kopečková, Patrick Bühler, Philipp Wolf, Huaizhong Pan, Hillevi Bauer, Ursula Elsässer-Beile et Jindřich Kopeček. « Biorecognition and Subcellular Trafficking of HPMA Copolymer−Anti-PSMA Antibody Conjugates by Prostate Cancer Cells ». Molecular Pharmaceutics 6, n^o 3 (22 avril 2009) : 959–70. http://dx.doi.org/10.1021/mp8002682.

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Tagawa, Scott T., Muhammad Junaid Niaz, Joseph Osborne, Shankar Vallabhajosula, Himisha Beltran, Lauren Christine Harshman, David M. Nanus et al. « Phase I/II dose-escalation trial of fractionated dose 177Lu-J591 plus 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 37, n^o 7_suppl (1 mars 2019) : TPS339. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.tps339.

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TPS339 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable dose-limiting myelosuppression. Recent prospective trials have shown efficacy and safety of 177Lu-PSMA-617 in mCRPC. Studies demonstrate different binding sites of J591 and PSMA-617 and co-administration leads to non-competitive additive binding and delivery of payloads to PSMA+ cells. As the pharmacokinetics and biodistribution of the 2 agents is mostly non-overlapping (other than tumor) and given our prior dose-response data, we hypothesize that delivery of the combination will yield higher tumor delivery with less off-target toxicity (i.e. better responses without increased toxicity). Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) with metastatic disease on CT/MRI or bone scan without limit of # prior therapies (excluding bone-targeted beta-emitting radioisotopes) provided adequate organ function will be enrolled. Pre-treatment 88Ga-PSMA-11 will be performed, but results are not used for eligibility. Treatment includes fractionated 177Lu-J591 at a fixed moderate dose with escalating doses of 177Lu-PSMA-617 (7.4 – 18.5 GBq per cycle, fractionated D1 and D15) in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade > 3 heme toxicity or grade > 2 non-heme toxicity. Following determination of recommended phase 2 dose (RP2D), the phase 2 portion will enroll in a 2-stage design. Primary endpoints: DLT and RP2D (ph 1) and PSA decline proportion (ph 2). Secondary endpoints include toxicity, radiographic response, PFS, rPFS, OS, CTC count changes. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu, tissue and circulating genomic assessment, immunologic assessment, and patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03545165.

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Kovar, Joy L., Lael L. Cheung, Melanie A. Simpson et D. Michael Olive. « Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice ». Prostate Cancer 2014 (2014) : 1–10. http://dx.doi.org/10.1155/2014/104248.

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Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds.In vivotargeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy.In vitroandin vivoblocking studies confirmed YC-27 specificity.In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.

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Sewell, T., G. Hernandez-Hoyos, R. A. Chenault, J. Wiens, J. Kumer, S. Natarajan, C. J. McMahan, P. A. Algate et J. W. Blankenship. « 319 Anti-PSMA X Anti-CD3 Bispecific Antibody Efficiently Redirects T Cell Cytotoxicity in Castrate-resistant Prostate Cancer Models ». European Journal of Cancer 48 (novembre 2012) : 98. http://dx.doi.org/10.1016/s0959-8049(12)72117-2.

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Tagawa, Scott T., Naveed Hassan Akhtar, Joseph Osborne, Paul J. Christos, Shankar Vallabhajosula, Stanley J. Goldsmith, Renee Kahn et al. « Phase II trial of 177lutetium radiolabeled anti-PSMA antibody J591 (177Lu-J591) for metastatic castrate-resistant prostate cancer (metCRPC) : Survival update and expansion cohort with biomarkers. » Journal of Clinical Oncology 31, n^o 6_suppl (20 février 2013) : 121. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.121.

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121 Background: A phase II trial in men with progressive metCRPC receiving a single dose of 177Lu-J591 at 65 mCi/m2 (15 pts) or 70 mCi/m2 (phase I MTD, 17 pts) was performed without selection for PSMA expression, suggesting a larger than expected dose-response (13 vs 47% >30% PSA decline respectively), leading to an expansion cohort to validate the response rate at 70 mCi/m2. Methods: Endpoints: to validate the PSA and/or measurable disease response at 70 mCi/m2, evaluate circulating tumor cell counts (CellSearch) and pre-treatment PSMA imaging with 111In-J591 in the expansion cohort, and examine overall survival (OS) for all pts. Results: 15 additional pts were treated. Expansion cohort demographics were similar to the initial cohorts, and PSA responses and toxicity were similar to the initial cohort treated at 70 mCi/m2 (see Table), with myelotoxicity improving in all following nadir at 1 month. More PSA declines and longer OS were seen at 70 mCi/m2. 12 of 15 pts had baseline and follow up CTC counts at 4-6 weeks: 66.7% had >50% decline and 25% were unchanged at 0 or 1 (one declined 27%). Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer > 30% PSA declines was seen with less intense PSMA imaging. Conclusions: Single dose 177Lu-J591 at70 mCi/m2 was generally well tolerated, with predictable, reversible myelosuppression, and demonstrates anti-tumor activity in pts with progressive metCRPC. A dose-response relationship was confirmed for both toxicity and activity, with improved response and OS at 70 mCi/m2. CTC declines are demonstrated. Selection of pts based upon non-invasive testing (PSMA imaging) may improve the therapeutic profile. Clinical trial information: NCT00195039. [Table: see text]

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Lutje, S., M. Rijpkema, G. M. Franssen, G. Fracasso, W. Helfrich, A. Eek, W. J. Oyen, M. Colombatti et O. C. Boerman. « Dual-Modality Image-Guided Surgery of Prostate Cancer with a Radiolabeled Fluorescent Anti-PSMA Monoclonal Antibody ». Journal of Nuclear Medicine 55, n^o 6 (3 avril 2014) : 995–1001. http://dx.doi.org/10.2967/jnumed.114.138180.

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Frigerio, Barbara, Gerben Franssen, Elena Luison, Alessandro Satta, Ettore Seregni, Marco Colombatti, Giulio Fracasso et al. « Full preclinical validation of the 123I-labeled anti-PSMA antibody fragment ScFvD2B for prostate cancer imaging ». Oncotarget 8, n^o 7 (30 décembre 2016) : 10919–30. http://dx.doi.org/10.18632/oncotarget.14229.

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Fleming, Mark T., Richard Cathomas, Daniel Peter Petrylak, Judy Sing-Zan Wang, Neil Harrison Bander, Francesca Zammarchi, Patrick H. van Berkel et al. « A phase 1/1b multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI3726 in patients with metastatic, castration-resistant prostate cancer who have received prior treatment with abiraterone or enzalutamide. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : TPS5088. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps5088.

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TPS5088 Background: Therapeutic advances have recently been achieved for patients with metastatic, castration-resistant prostate cancer (mCRPC) due to abiraterone acetate (ABI) and enzalutamide (ENZ). However, virtually all patients with mCRPC eventually progress in their disease, and further treatment options are limited. Prostate-specific membrane antigen (PSMA) is highly expressed in nearly all prostate cancers, and its expression is highest in mCRPC. MEDI3726 is an antibody-drug conjugate composed of anti-PSMA antibody derived from J591, site-specifically conjugated to the cytotoxic, DNA cross-linking, pyrrolobenzodiazepine dimer. MEDI3726 has demonstrated potent and specific in vitro and in vivo antitumor activity in human prostate cancer-derived preclinical models with different expression levels of PSMA. Methods: This is a first-in-human, phase 1/1b, multicenter, open-label, dose escalation and dose expansion study in patients who have received prior treatment with ABI or ENZ, with or without prior taxane-based chemotherapy in the mCRPC setting (NCT02991911). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or maximum administered dose of MEDI3726. The secondary objectives are to evaluate MEDI3726 for its antitumor activity (based on a composite response according to RECIST Version 1.1, a reduction in prostate-specific antigen level of 50% or more compared to baseline, or a conversion in the circulating tumor cell count [defined as a reduction from ≥5 cells/7.5 mL blood to < 5 cells/7.5 mL blood]), safety and tolerability in combination with ENZ, pharmacokinetics alone and in combination with ENZ, and immunogenicity. Recruitment is ongoing for this study, which has an estimated total target enrollment of 224 patients. Clinical trial information: NCT02991911.

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Clark, CE, AF Chall, JC Stagg, V. Sittaramane, RL Quirino, AC Mixson et WE Gato. « Investigating the toxicology of intramuscular injected multiwalled carbon nanotubes conjugated antibody (CNT-Ab) in mice followed by microwave hyperthermia ». Toxicology Research and Application 5 (1 janvier 2021) : 239784732110015. http://dx.doi.org/10.1177/23978473211001580.

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Carbon nanotubes bound to tumor specific antibodies offer specific treatment for cancer cells without affecting surrounding tissue. The present study seeks to affirm the initial results of CNTs in cancer therapy by investigating the toxicological effect in mice injected with CNT-Ab followed by microwave hypothermia. We were particularly interested in evaluating the biodistribution, toxicity, and immune response that may be elicited from CNT-Ab exposure in mice. 4–5 week old mice (C57BL/6) were injected with various concentrations and combinations of multiwalled carbon nanotubes (MWCNT) conjugated with specific prostate-specific membrane antigen (PMSA) antibodies. After 1-week post-injection, mice were sacrificed followed by the collection of blood separated into serum, liver, kidney and other tissues for further analysis. Serum total protein concentration across the treatment groups was varied. No significant changes in albumin levels were detected when compared to the control group (No Treatment). Group YE (.125 mg/ml anti-PSMA-MWCNT + Microwave) was found to have consistently high blood serum analyte levels, indicating impaired liver and kidney function. Likewise, groups YB (Microwave only), YF [.5 mg/ml anti-PSMA-MWCNT (No Microwave)], and YG (.5 mg/ml plain MWCNT + Microwave) seemed to show indications of impaired liver function. Analysis of gene expression revealed a significant impact on the NF-KB inflammatory response pathway. NF-KB gene was up-regulated relative to controls in all treatment groups. These results seem to suggest marginal toxicity from the injection of CNT-Ab followed by microwave hyperthermia in mice subjects.

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Gonzalez-Valdivieso, Juan, Yanping Yang, Yogindra Vedvyas, Yago Alcaina et Moonsoo M. Jin. « Abstract 5577 : PSMA targeting CAR T cell immunotherapeutic strategy for prostate cancer ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5577. http://dx.doi.org/10.1158/1538-7445.am2022-5577.

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Abstract Introduction: Prostate cancer is the third most frequent cause of cancer-related death in men worldwide. Since prostate-specific membrane antigen (PSMA) shows a significant overexpression on prostatic cancer cells, PSMA can be considered a promising target for prostate cancer imaging and treatment. Although chimeric antigen receptor (CAR) T cells have shown great clinical outcomes in hematological malignancies, there is still limited efficacy in solid tumors due to the lack of tumor-specific antigens, low T cell infiltration in the tumors, immune suppressive tumor microenvironment, and on-target off-tumor toxicity in healthy tissues. The antigen recognition module of CAR T cells is usually a single-chain variable fragment (scFv). In contrast, the variable domains of heavy-chain antibodies (VHH) are small, stable, single-domain antibody fragments with high affinity and do not require the supramolecular assembly. Severe fatalities recently halted clinical trials of PSMA CAR T cells, so affinity tuning may be required to avoid CAR T targeting normal tissues. Here, we developed VHH-based CAR T cells targeting PSMA, able to co-express human somatostatin receptor 2 (SSTR2) actioning as a PET reporter for tracking CAR T cell distribution, as an immunotherapeutic strategy for prostate cancer. Methods: Primary human T cells were isolated and transduced with PSMA CAR lentivirus at 24 and 48 hours after activation with anti-CD3/CD28 Dynabeads. Mouse models of 8505C cell line transduced to overexpress PSMA were utilized to test the efficacy of CAR T cells. Tumor growth was monitored regularly by bioluminescence imaging. PET/CT imaging was performed to monitor T cell localization and biodistribution using ¹⁸F-NOTA-octreotide radiotracer targeting SSTR2 introduced in CAR T cells. Results: By alanine substitution of CDR3 in the VHH, we identified several low affinity candidates. The affinity of the VHH-based PSMA CAR was determined to be 22 nM by a saturation binding assay using monomeric human PSMA protein. PSMA CAR expression in primary human T cells was higher than 90%. Compared to non-treated mice, PSMA targeting CAR T cells led to tumor reduction and improved survival in animal models. Moreover, high levels of T cell infiltration and localization in tumor tissues were found, based on PET/CT imaging. Considering possible treatment-associated toxicities, which led to 2 patient deaths and the halt of one phase 1 trial of PSMA CAR T cells, we will affinity tune VHH-based CAR to improve the safety profile. Thus, additional studies will be performed to test both activity and safety of affinity variants of PSMA CAR T cells. Conclusions: We developed PSMA targeting CAR T cells able to induce potent and specific killing of prostate cancer cells. This strategy demonstrated significant therapeutic efficacy in vivo against animal models. Therefore, CAR T cells targeting PSMA may be a promising treatment strategy for patients with prostate cancer. Citation Format: Juan Gonzalez-Valdivieso, Yanping Yang, Yogindra Vedvyas, Yago Alcaina, Moonsoo M. Jin. PSMA targeting CAR T cell immunotherapeutic strategy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5577.

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Akhtar, N. H., D. M. Nanus, S. Vallabhajosula, J. Osborne, H. Beltran, L. Tyrell, K. Nadeau et al. « Radiolabeled anti–prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer (CRPC). » Journal of Clinical Oncology 29, n^o 15_suppl (20 mai 2011) : e15186-e15186. http://dx.doi.org/10.1200/jco.2011.29.15_suppl.e15186.

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Markowski, Mark Christopher, Deepak Kilari, Mario A. Eisenberger, Rana R. McKay, Robert Dreicer, Mohit Trikha, Elisabeth I. Heath, Jing Li, Pamela D. Garzone et Travis S. Young. « Phase I study of CCW702, a bispecific small molecule-antibody conjugate targeting PSMA and CD3 in patients with metastatic castration-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : TPS5094. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps5094.

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TPS5094 Background: CCW702 is a novel bispecific antibody comprised of a small molecule imaging agent ligand (DUPA) with specificity for prostate specific membrane antigen (PSMA) conjugated to an anti-CD3 antibody via an unnatural amino acid. This format has the structure of an antibody drug conjugate with the activity of a CD3-engaging bispecific antibody. The design of CCW702 was leveraged to optimize the structure and function of T cell redirected cytotoxicity against PSMA-positive prostate cancer tumors in preclinical development. Methods: This is a first-in-human, open-label, multi-center phase 1 study evaluating the safety and tolerability of CCW702 when administered via subcutaneous (SC) injection in men with mCPRC. This study will be conducted in two parts: Part I, a dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD); Part II, a dose expansion to determine efficacy at the R2PD. Safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy will be evaluated. Efficacy will be assessed by change in circulating tumor cells (CTC), PSA50 response rate, and objective tumor response by RECIST v1.1. Key biomarkers include characterization of CTC, T cell phenotyping in peripheral blood, chemokines and cytokines over time, and evaluation of available tumor biopsies by IHC. Key inclusion criteria include men age ≥ 18 years with histologically or cytologically confirmed adenocarcinoma who, in the metastatic setting, have progressed on at least one novel AR-targeted therapy. Up to 1 prior chemotherapy regimen is allowed. This study will enroll 20-30 patients in Part 1 and approximately 40 patients in Part 2. The study opened in December 2019 and is currently enrolling in the dose escalation phase. Clinical trial information: NCT04077021.

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Lankoff, Anna, Malwina Czerwińska, Rafał Walczak, Urszula Karczmarczyk, Kamil Tomczyk, Kamil Brzóska, Giulio Fracasso, Piotr Garnuszek, Renata Mikołajczak et Marcin Kruszewski. « Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy—Part II. Toxicity, Pharmacokinetics and Biodistribution ». International Journal of Molecular Sciences 22, n^o 11 (27 mai 2021) : 5702. http://dx.doi.org/10.3390/ijms22115702.

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Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients. Despite introduction of novel therapies, the mortality rate remains high. An attractive alternative for extension of the life of mCRPC patients is PSMA-based targeted radioimmunotherapy. In this paper, we extended our in vitro study of 223Ra-labeled and PSMA-targeted NaA nanozeolites [223RaA-silane-PEG-D2B] by undertaking comprehensive preclinical in vitro and in vivo research. The toxicity of the new compound was evaluated in LNCaP C4-2, DU-145, RWPE-1 and HPrEC prostate cells and in BALB/c mice. The tissue distribution of 133Ba- and 223Ra-labeled conjugates was studied at different time points after injection in BALB/c and LNCaP C4-2 tumor-bearing BALB/c Nude mice. No obvious symptoms of antibody-free and antibody-functionalized nanocarriers cytotoxicity and immunotoxicity was found, while exposure to 223Ra-labeled conjugates resulted in bone marrow fibrosis, decreased the number of WBC and platelets and elevated serum concentrations of ALT and AST enzymes. Biodistribution studies revealed high accumulation of 223Ra-labeled conjugates in the liver, lungs, spleen and bone tissue. Nontargeted and PSMA-targeted radioconjugates exhibited a similar, marginal uptake in tumour lesions. In conclusion, despite the fact that NaA nanozeolites are safe carriers, the intravenous administration of NaA nanozeolite-based radioconjugates is dubious due to its high accumulation in the lungs, liver, spleen and bones.

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Tagawa, Scott T., Shankar Vallabhajosula, Yuliya Jhanwar, Karla V. Ballman, Amy Hackett, Lauren Emmerich, John Babich et al. « Phase I dose-escalation study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 36, n^o 6_suppl (20 février 2018) : TPS399. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.tps399.

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TPS399 Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies (excluding beta-emitting bone-targeted radioisotopes) provided adequate organ function will undergo imaging with 68Ga-PSMA-11 PET/CT followed by a single dose of 225Ac-J591. Single-subject cohorts will be enrolled until grade > 1 attributable toxicity, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to 93.3 KBq/kg of 225Ac with fixed 20 mg J591. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS, and patient reported outcomes (FACT-P and BPI-SF). Correlatives include baseline/follow up PSMA imaging, CTC count (CellSearch) changes, tissue and circulating genomic assessment, and immune studies. Enrollment began in October, 2017. Clinical trial information: NCT03276572.

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Lebenthal, Justin M., Michael Sun, Jones T. Nauseef, Muhammad Junaid Niaz, Dunya Imad, Paul J. Christos, Escarleth Fernandez et al. « Pilot study of anti-prostate-specific membrane antigen (PSMA) antibody J591 for men with metastatic castration-resistant prostate cancer (mCRPC) and unfavorable circulating tumor cell (CTC) count. » Journal of Clinical Oncology 39, n^o 6_suppl (20 février 2021) : 120. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.120.

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120 Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was observed to have CTC count decline following imaging with 111In-J591, so a prospective study was launched to test the hypothesis that “naked” J591 leads to CTC count decline. Methods: In a Simon 2-stage dose de-escalation study, men with progressive mCRPC and unfavorable CTC count (CellSearch > 4) received a single dose of J591. Initial dose cohort 300 mg with de-escalation to 20 mg. CTC count was re-assessed 4, 8, and 12 weeks following therapy along with PSA and standard imaging. An optional PSMA PET was included prior to treatment. The primary endpoint was proportion of subjects with conversion to favorable CTC count ( < 5 CTCs/7.5 mL blood) and/or > 30% decline from baseline within 12 weeks post-treatment. Results: 10 men were enrolled, 9 of whom were evaluable (1 died of progressive mCRPC prior to post-treatment CTC count). Median age was 71.5 years (range 60-81), 78% had prior chemo, ECOG PS 1 in 45% and 2 in 55%. 7 of 9 (78%) evaluable subjects were Halabi CALGB prognostic poor risk category and 2 (22%) intermediate. 6 of 9 had pre-treatment PSMA PET/CT (three 89Zr-J591 and three 68Ga-PSMA11). Though not required, all scans showed > 1 lesion with SUVmax > liver SUV (range 9.12-70.15). 2 of 6 in the 300 mg cohort had CTC count decline; 1 of 6 converted to favorable count (9 to 0 with decrease of 35 to 12 in other). 3 were treated with 20 mg; 1 had CTC count decline of 316 to 112, but 0 converted to favorable count. Across both cohorts, 3 of 9 had a CTC count decline at any point in time, ranging from 65-100% decline. With the pre-specified 2-stage design, enrollment was halted for futility based upon the primary endpoint of 12-week CTC count. PSA values post-treatment increased in 8 (89%) patients and remained unchanged in 1 (11%) patient. Conclusions: Single-agent anti-PSMA antibody J591 may lead to decline in CTC count, though the study did not meet its primary endpoint. A combination or maintenance approach might be preferable and is worthy of exploration.

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Li, Hong, You Li, Cheng Wang, Shouye Wang et Mitchell Ho. « Highlights of 2019 Protein Engineering Summit (PEGS) in Boston, USA : advancing antibody-based cancer therapies to the clinic ». Antibody Therapeutics 2, n^o 4 (1 octobre 2019) : 79–87. http://dx.doi.org/10.1093/abt/tbz010.

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Abstract The 15th Annual Protein Engineering Summit (PEGS) organized by Cambridge Healthtech Institute was held in Boston, USA, from 8 to 12 April 2019. This report highlights the presentations in the Oncology Stream of this meeting with a focus on bispecific antibodies (BsAbs). A variety of BsAb formats with different target antigens (CD3, CTLA4, PD-1, PD-L1, EGFR, HER2, BCMA, CD19, CD20, CD38, CD123, TGFβ, PSMA, etc.) have been discussed, in which the T-cell engaging (anti-CD3) BsAb is the most studied construct to exhibit promising immunotherapeutic activities. The BsAb formats include IgG-like structures or antibody fragments composed of antigen-binding sites only. Preclinical and clinical data from different BsAbs demonstrated the potential therapeutic applications in various solid tumors and hematological malignancies. The ongoing development of BsAb formats will help overcome current clinical issues, such as tumor selectivity and antigen coverage. This report also covers several presentations about emerging targets (e.g. mesothelin, CD47) and new technologies in the field of antibody engineering and therapeutics.

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Lim, Emerson A., Michael Thomas Schweizer, Kim N. Chi, Rahul Raj Aggarwal, Neeraj Agarwal, James L. Gulley, Edward F. Attiyeh et al. « Safety and preliminary clinical activity of JNJ-63898081 (JNJ-081), a PSMA and CD3 bispecific antibody, for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 40, n^o 6_suppl (20 février 2022) : 279. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.279.

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279 Background: PSMA expression is increased in response to anti-androgen therapies and is a promising therapeutic target for the treatment of prostate cancer (PCa). JNJ-081 is a bispecific antibody with one arm binding PSMA on cancer cells and the other binding CD3 on T-cells to promote anti-tumor activity. Methods: This Phase 1 Dose Escalation Study evaluated JNJ-081 in mCRPC participants (pts) who progressed after novel androgen targeting therapy (eg, abiraterone, enzalutamide or apalutamide). Prior chemotherapy was permitted. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route. Dose escalation followed a continuous reassessment method based on a Bayesian regression model. The primary endpoint to determine the recommended phase 2 dose (RP2D) was based on safety. Pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activity were also evaluated. Cytokine release syndrome (CRS) was graded by CTCAE V5. Results: As of 10 May 2021, 39 pts were dosed in 10 cohorts ranging from 0.1 µg/kg to 3 µg/kg IV and from 3 µg/kg to 60 µg/kg SC. Premedications included high dose corticosteroids. Step-up priming was implemented at higher SC doses. Most common treatment-emergent AEs were CRS (65%), fatigue (49%) and nausea (43%). 2 pts developed DLTs of Grade (G) 3 or G4 transaminases increased, 1 each at 30 µg/kg SC and priming with 10 µg/kg SC then 55 µg/kg SC, respectively. Both DLTs were in conjunction with or followed an episode of G2 CRS. SC route as well as step-up priming helped mitigate CRS and infusion-related reaction (IRR) during escalation to higher doses: at 3 µg/kg IV, 4 of 5 pts had G2 CRS or IRR; at 30 µg/kg SC, 3 of 4 pts had G2 CRS; priming with 10 µg/kg then 55 µg/kg SC, 4 of 5 pts had G2 CRS. Injection site reactions (G1 or G2) occurred in 24 of 26 pts treated via SC JNJ-081. No treatment related death was reported. Transient PSA decreases were observed at treatment doses greater than 30 µg/kg SC. Two subjects treated with 55 µg/kg had PSA decreases > 50%. No radiographic responses were observed. PK of JNJ-081 was linear over the dose range of 3-60 µg/kg following SC administration. SC bioavailability was approximately 25%. Anti-drug antibodies (ADA) were detected in 2 of 12 subjects treated by IV administration and 14 of 23 pts treated by SC administration. ADA resulted in loss of exposure in some SC pts. Intrapatient dose escalation in 3 pts did not overcome the reduced exposure after ADA seropositivity. Conclusions: JNJ-081 demonstrated transient decreases in PSA in mCRPC patients. Grade 2 CRS was observed at higher doses and was partially mitigated by SC and step-up dosing. ADA resulting in decreased exposure occurred in the majority of pts treated SC. PSMA remains a potential therapeutic target for T-cell redirection for the treatment of PCa. Clinical trial information: NCT03926013.

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Morris, Michael J., Stephen Barnett Solomon, Jeremy C. Durack, Joseph A. O' Donoghue, Serge K. Lyashchenko, Ruan Shutian, Jorge A. Carrasquillo et al. « Pathologic correlation of 89Zr-Df-IAB2M antiprostate-specific membrane antigen (PSMA) minibody in patients with metastatic prostate cancer. » Journal of Clinical Oncology 33, n^o 7_suppl (1 mars 2015) : 220. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.220.

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220 Background: IAB2M is a novel anti-PSMA minibody (Mb) based on the humanized J591 antibody that targets the extracellular domain of PSMA. The Mb has been engineered to remove Fc-Rn interactions and reduce the molecular weight relative to J591. The result is faster blood pool clearance, for a more favorable imaging schedule, while retaining bivalent targeting of PSMA. We have previously reported on the pharmacokinetics, dosimetry, and lesion uptake of IAB2M(Pandit-Taskar et al, WMIS 2014). Here we report the correlation between imaging and pathology of biopsies of PSMA avid lesions. Methods: Following standard imaging (SI) of CT/MRI, bone scintigraphy (BS), and FDG PET, 5 mCi of 89Zr-Df-IAB2M was administered intravenously. Escalating minibody doses of 10, 20, and 50 mg were delivered, with cohort expansion at 10 and 20 mg. Whole body PET/CT scans were serially performed at various time points:1-2 h, 24 h, 48 h, and 72-144 h post injection. Metastases identified on PET were confirmed, where possible, with bx’s in the following preference: concordant IAB2M and FDG positivity, IAB2M, and FDG mismatch, or a mismatch between SI and any PET. Results: 24 patients (pts) with metastatic prostate cancer were scanned (11 at 10, 7 at 20, and 6 at 50 mg Mb doses). A total of 15 bxs (7 soft tissue, 8 bone) were performed on 14 pts; the histopathologic correlation is summarized in the table below. 13 lesions were identified by IAB2M, 11 by FDG, and 14 by SI. Of these, 12/13 (92.3%), 10/11 (90.9%), 12/14 (85.7%) were biopsy positive for cancer, respectively. 2 bone lesions were not identified by IAB2M, evident on other imaging modalities, and were both neg by bx. Overall bx concordance (pos/pos, neg/neg) with imaging was: IAB2M 14/15 (93%) vs. BS/CT 13/15 (86%) vs. FDG 12/15 (80%). Conclusions: An ongoing analysis of IAB2M imaging showed a high concordance with pathologic findings in patients with metastatic prostate cancer. Clinical trial information: NCT01923727. [Table: see text]

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de Bono, Johann S., Hendrik-Tobias Arkenau, Eelke H. Gort, Lot L. Devriese, Elisa Fontana, Daan G. Knapen, Crescens Tiu et al. « Abstract CT207 : A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA) ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : CT207. http://dx.doi.org/10.1158/1538-7445.am2022-ct207.

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Abstract Humabodies* are fully human VH antibody components that can be connected by short peptide linkers to make multi-specific therapeutics. CB307 is a tri-specific Humabody targeting prostate specific membrane antigen (PSMA/FOLH1), CD137 (4-1BB/TNFSF9) and human serum albumin (HSA). Unlike CD3 targeting bispecific compounds, stimulation of CD137 on T cells can promote T cell cytotoxicity, proliferation, survival and memory T cell formation without compromising safety, including cytokine release syndrome (CRS). In addition, HSA binding assists CB307 penetration into the tumor since albumin is enriched in the tumor microenvironment. Several cancers including prostate cancer and lung cancer are known to have PSMA expression. The objectives of the POTENTIA study are to determine the maximum tolerated dose (MTD) and pharmacokinetics of CB307 and to assess preliminary anti-tumor activity in patients with PSMA+ solid tumor. Methods: The phase 1 study consists of dose escalation (part 1) and cohort expansion (part 2) components, and the study is currently enrolling patients in part 1 without dose limiting toxicities (DLTs). The dose escalation uses an accelerated titration design (ATD) and a modified continual reassessment method (mCRM) to guide the MTD and the recommended phase 2 dose (RP2D). The key inclusion criteria are as follows: histologically confirmed advanced or metastatic PSMA expressing solid tumors determined by immunohistochemistry; not amenable to standard-of-care; RECIST measurable disease or increased serum PSA at baseline (for bone metastasis-only prostate cancer). The key exclusion criteria are patients with brain metastases; patients who have discontinued previous immunotherapy due to intolerable immune-related adverse events; patients with acute infections or autoimmune diseases. Cohort expansion uses the same eligibility criteria, however, at least 3 patients with castration-resistant prostate cancer harboring either BRCA1, BRCA2, ATM and/or CDK12 mutation(s) will be enrolled. CB307 is administered intravenously every week. PSMA-PET scan and tumor biopsy are taken to understand the mechanism of action of CB307 as well as a change of PSMA expression during CB307 treatment. NCT04839991 * “Humabody” is a registered trademark ® of Crescendo Biologics Ltd. Citation Format: Johann S. de Bono, Hendrik-Tobias Arkenau, Eelke H. Gort, Lot L. Devriese, Elisa Fontana, Daan G. Knapen, Crescens Tiu, Anja Williams, Derk Jan A. de Groot, Ulug M. Gunaydin, Phillip Bartlett, Andrew J. Pierce, Philip Bland-Ward, Kenji Hashimoto, E.G. Elisabeth de Vries. A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT207.

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Huang, Colin T., Xin Guo, Cyril Bařinka, Shawn E. Lupold, Martin G. Pomper, Kathleen Gabrielson, Venu Raman, Dmitri Artemov et Sudath Hapuarachchige. « Development of 5D3-DM1 : A Novel Anti-Prostate-Specific Membrane Antigen Antibody-Drug Conjugate for PSMA-Positive Prostate Cancer Therapy ». Molecular Pharmaceutics 17, n^o 9 (17 août 2020) : 3392–402. http://dx.doi.org/10.1021/acs.molpharmaceut.0c00457.

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Tagawa, S. T., S. Parmar, J. Pena, K. Petrillo, D. Matulich, J. Selzer, S. Vallabhajosula, S. J. Goldsmith, N. H. Bander et D. M. Nanus. « Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 in patients (pts) with metastatic castration-resistant prostate cancer (metCRPC) ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : e16004-e16004. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16004.

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e16004 Background: Reversible myelosuppression is the dose-limiting toxicity of radioimmunotherapy (RIT). Cases of marrow damage, including myelodysplasia and acute leukemia have been reported with the RIT most used to date (that targeting CD20 in Non- Hodgkin's lymphoma), though no statistically significant association exists. In addition, post-RIT chemotherapy (chemo) may theoretically be limited. We have treated metCRPC pts with anti-PSMA RIT since 2000 and analyzed post-therapy outcomes. Methods: Follow-up across 4 prospective phase I and II trials utilizing 177Lu-J591 and 90Y-J591 was performed. Quality of hematologic recovery from post-RIT myelosuppression was documented. Administration of pre- and post-RIT chemo was analyzed. Specific searches for subsequent myelodysplasia and/or leukemia were performed. Results: Median age of the 109 treated pts is 70 (range 47–88). Entry criteria for all trials included progressive metCRPC, PS < 2, normal baseline neutrophil and platelet counts, and hemoglobin > 10 g/dL. 80 received 177Lu-J591 at cumulative doses ranging from 10–120 mCi/m2 and 29 received 90Y-J591 at cumulative doses of 5–40 mCi/m2. 43% received at least 1 line of pre-RIT chemo, 53% received at least 1 line of post-RIT chemo, and 20% have never received chemo to date. All pts with adequate performance status received chemo except per pt choice. Excluding re-treated pts, 98% and 87% of assessable pts had full recovery of neutrophils and platelets respectively. Of the remaining, all but 4 recovered to Gr 1 neutropenia and/or thrombocytopenia. The most common reason for lack of complete hematologic recovery was CRPC progression in bone marrow (16 pts with persistent or recurrent myelosuppression underwent bone marrow biopsy). No cases of post-RIT myelodysplasia and/or leukemia were discovered. Conclusions: Anti-PSMA radioimmunotherapy is well-tolerated with efficacy previously reported. While follow-up is ongoing, reports of irreversible bone marrow damage appear unfounded and all patients with intact performance status willing to undergo post-RIT chemotherapy are able to receive it. [Table: see text]

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Bander, Neil H., Matthew I. Milowsky, David M. Nanus, Lale Kostakoglu, Shankar Vallabhajosula et Stanley J. Goldsmith. « Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer ». Journal of Clinical Oncology 23, n^o 21 (20 juillet 2005) : 4591–601. http://dx.doi.org/10.1200/jco.2005.05.160.

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Purpose To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of 177Lutetium-labeled anti–prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) in patients with androgen-independent prostate cancer (PC). Patients and Methods Thirty-five patients with progressing androgen-independent PC received 177Lu-J591. All patients underwent 177Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. Results Thirty-five patients received 177Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m2, and the 70-mCi/m2 dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m2 was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing ≥ 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months). Conclusion The MTD of 177Lu-J591 is 70 mCi/m2. Multiple doses of 30 mCi/m2 are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.

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