Статті в журналах: "Monoclonal antibody, immunocytokine, immunotherapy"

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Singh, Harjeet, Lisa Marie A. Serrano, Simon Olivares, Michael Jensen, George McNamara, David Colcher, Andrew Raubitschek, and Laurence J. N. Cooper. "Combining Immunocytokine with Adoptive Immunotherapy To Treat B-Lineage Lymphomas." Blood 106, no. 11 (November 16, 2005): 343. http://dx.doi.org/10.1182/blood.v106.11.343.343.

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Abstract Lineage-specific cell-surface molecules, such as CD19 and CD20 on B-lineage malignancies are the targets for immunotherapies. However, the therapeutic success of CD19-specific T-cell therapy is predicted to be dependent on the continued persistence of adoptively transferred T cells. It is well-recognized that exogenous IL-2 can help sustain the in vivo persistence of ex vivo-propagated CD8+ T cells. Therefore, in order to target biologically active IL-2 to the tumor microenvironment, we have used an immunocytokine (ICK) to deliver this cytokine to binding-sites of a CD20-specific monoclonal antibody (mAb) on malignant B cells. This anti-CD20-IL2 ICK was based on the Leu16 anti-CD20 mAb that was dehumanized to remove T-helper epitopes. Flow cytometry demonstrated that anti-CD20-IL2 ICK specifically bound to CD20+ tumor and IL-2R+ T cells. Thus, we investigated the ability of this ICK to improve the persistence of adoptively transferred B-lineage lymphoma-specific T cells. To obtain CD19-specific T cells that could be non-invasively imaged in vivo, we used non-viral gene transfer to introduce a DNA plasmid to co-express both a CD19-specific immunoreceptor (designated CD19R) and firefly luciferase (ffLuc). The CD19R combines antibody recognition with T-cell effector functions mediated through CD3-ζ . The genetically modified T cells were characterized as differentiated CD8+ effector cells expressing the IL-2 receptor complex, which specifically recognize and lyse CD19+ lymphoma targets. To model the survival of adoptively transferred T cells and treatment of lymphoma in vivo, we generated a CD20+CD19+ ARH-77 tumor line expressing the Renilla luciferase (rLuc) reporter gene. Our data demonstrate that this tumor line is resistant to a CD20-specific mAb, Rituximab, in vivo. Sub-optimal doses of CD19R+ffLuc+ CD8+ T cells, which do not cause complete eradication of tumor by themselves, were infused along with anti-CD20-IL2 ICK and control ICK (with irrelevant specificity) in NOD/scid mice bearing xenografts of the rLuc+ tumor. In vivo non-invasive bioluminescent imaging (BLI) was used to longitudinally measure the persistence of ffluc+ T cells and growth of rluc+ tumor. In our mouse model, the T cells persisted significantly (p<0.05) longer in the mice treated with anti-CD20-IL2 ICK, compared to mice receiving the ICK with an irrelevant specificity. This improvement in T-cell persistence translated into augmented anti-tumor activity (Figure). These results suggest that combining tumor-specific ICK with tumor-specific T cells may improve the outcome of immunotherapy. Since Phase I trials are underway using anti-CD20-IL2 ICK and CD19-specific T cells as monotherapy, our results warrant clinical trials using combination of these immunotherapies. Synergistic anti-tumor effect of tumor-specific ICK and tumor-specific T cells. Serial pseudo-color images represent light intensity from rluc(+) ARH-77 cells in NOD/scid mice before and after immunotherapies. The irrelevant immunocytokine has specificity for GD2 which is not expressed on tumor cells. Synergistic anti-tumor effect of tumor-specific ICK and tumor-specific T cells. Serial pseudo-color images represent light intensity from rluc(+) ARH-77 cells in NOD/scid mice before and after immunotherapies. The irrelevant immunocytokine has specificity for GD2 which is not expressed on tumor cells.

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Aiken, Taylor, Julie Voeller, Amy Erbe, Alexander Rakhmilevich, and Paul Sondel. "458 Antitumor mechanisms of local radiation and combination immunotherapy in an immunologically cold model of neuroblastoma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A486. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0458.

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BackgroundThe standard treatment for high-risk neuroblastoma includes a combination immunotherapeutic approach consisting of IL-2, GM-CSF, and monoclonal antibodies directed against GD2, a disialoganglioside preferentially expressed in neuroblastoma and melanoma (1). We recently described an effective a preclinical in-situ vaccination strategy combining local radiation therapy (RT), IL-2-linked to anti-GD2 monoclonal antibody (intratumoral immunocytokine, IT-IC), checkpoint inhibition (anti-CTLA4), and drivers of innate immunity (anti-CD40 and CpG) (2). This strategy is effective in curing mice with immunologically-cold neuroblastoma. We sought to better characterize the anti-tumor mechanisms that mediate this effect.MethodsMice bearing GD2-expressing, immunologically-cold neuroblastoma tumors (9464D-GD2) were treated with 12Gy RT and combination immunotherapy (IT-IC, anti-CTLA-4, CpG, anti-CD40) over 12 days as previously described (2). Depletion of individual immune cell sets during treatment was achieved by depleting monoclonal antibodies and confirmed by flow cytometry. T-cell receptor deficient (TCR KO) mice were used to confirm findings in T-cell depletion experiments. 9464D-GD2 parental cells have low MHC-I expression; subclones with low and moderate MHC Class I expression were obtained by flow cytometry sorting and the impact of MHC class I expression on immune cell infiltrate and survival was assessed.ResultsThe effectiveness of RT and combination immunotherapy was not significantly reduced by NK or T cell depletion, and TCR KO mice had similar tumor growth and survival to mice that underwent T-cell depletion. Moderate MHC class I expression did not slow tumor growth or improve survival in mice bearing 9464D-GD2 tumors (over those with low MHC-I) following treatment. Moderate MHC class I expression also did not alter individual immune cell subsets in treated tumors. Overall, increased infiltration of CD8 T-cells, CD4 T-cells, and depletion of T regulatory cells was observed in all treated tumors (p<0.05).Abstract 458 Figure 1Effect of MHC class I expression on response to RT and combination immunotherapy (IT-IC, anti-CTLA4, anti-CD40, CpG). A) Increased MHC class I expression in 9464D-GD2 derived tumors did not alter tumor growth or survival following treatment. B) Increased MHC class I expression did not alter immune subsets following treatment of 9464D-GD tumors with radiation and combination immunotherapy. Increased numbers of CD8+ and CD4+ T-cells was observed with both moderate and absent MHC class I expression. T regulatory cells were also effectively depleted in both treated groupsConclusionsTreatment with RT and combination immunotherapy (IT-IC, anti-CTLA4, anti-CD40, CpG) may act through mechanisms that are MHC class I, NK-cell and T-cell independent. Further investigation of the role of innate immunity and myeloid subsets in this scenario is warranted.AcknowledgementsResearch reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32 CA090217.ReferencesYu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma. New England Journal of Medicine 2010;363:1324–34Voeller J, Erbe AK, Slowinski J, Rasmussen K, Carlson PM, Hoefges A, et al. Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. Journal for Immunotherapy of Cancer 2019;7:13

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Alderson, Kory L., and Paul M. Sondel. "Clinical Cancer Therapy by NK Cells via Antibody-Dependent Cell-Mediated Cytotoxicity." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/379123.

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Natural killer (NK) cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs). Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs) designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings.

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Aiken, Taylor J., David Komjathy, Mat Rodriguez, Arika Feils, Stephen D. Gillies, Amy K. Erbe, Alexander L. Rakhmilevich, and Paul M. Sondel. "Short-course neoadjuvant intratumoral immunotherapy establishes immunologic memory in murine melanoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21561-e21561. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21561.

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e21561 Background: GD2 is disialoganglioside preferentially expressed in neuroblastoma and melanoma and anti-GD2 directed therapies are used clinically in neuroblastoma, with ongoing clinical trials in melanoma. We are currently developing an in situ vaccination approach using intratumoral (IT) delivery of an immunocytokine (IC) consisting of IL-2 linked to an anti-GD2 monoclonal antibody. While IT-IC monotherapy does not cure mice bearing established B78 melanoma tumors, it is effective when combined with local radiation therapy (RT). Here, we tested whether short course IT-IC monotherapy prior to surgical resection could result in a robust adaptive immune response preventing tumor recurrence following rechallenge after surgery. Methods: Mice bearing 50-100mm3 GD2-expressing melanoma (B78) tumors were treated with a 5-day course of 50μg IT-IC and complete surgical resection was performed 3 days following the final treatment. The immune infiltrate of resected tumors was assessed by flow cytometry. Rechallenge experiments consisted of either 2x106 B78 cells injected into the contralateral flank or 2x105 B16-GD2 cells injected via tail vein for pulmonary metastasis rechallenge. Results: IT-IC treated tumors had fewer viable tumor cells, increased CD8 T-cells, and an improved CD8:Treg ratio. Rejection of B78 contralateral flank rechallenge (implanted 40 days following surgical resection of the primary tumor) was observed in 78% (7/9) of mice treated with IT-IC compared to 50% (5/10) that received surgery alone and 0% (0/5) of naïve mice. Immunologic memory was potent in neoadjuvant-treated mice early after surgery, with all mice (5/5) rejecting contralateral B78 rechallenge that occurred on the day of surgery compared to 0% (0/5) in both surgery-alone and naïve mice. Neoadjuvant IT-IC also prevented the development of B16-GD2 lung metastasis compared to naïve mice or the surgery-alone group (when the IV injected experimental metastases were given 80 days following surgery). Conclusions: While ineffective in curing large B78 melanoma flank tumors as monotherapy, mice receiving neoadjuvant IT-IC developed robust immunologic memory preventing recurrence following surgery. The memory response was present as early as the day of surgery and was sufficient to prevent pulmonary metastasis. IT-IC should be further investigated as a neoadjuvant therapy for preventing recurrence in high-risk settings.

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Schliemann, Christoph, Niklas Börschel, Christian Schwöppe, Rüdiger Liersch, Torsten Kessler, Martin Dreyling, Wolfram Klapper, et al. "Targeting Interleukin-2 to the Neovasculature Potentiates Rituximab‘s Activity Against Mantle Cell Lymphoma in Mice." Blood 120, no. 21 (November 16, 2012): 3716. http://dx.doi.org/10.1182/blood.v120.21.3716.3716.

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Abstract Abstract 3716 Introduction: Antibody-based tumor targeting strategies promise to specifically target anti-neoplastic agents (e.g. radionuclides, drugs, cytokines) to the tumor site while sparing healthy tissues. In this context, the selective delivery of bioactive molecules to the vasculature seems particularly attractive, considering the fact that antigens expressed in blood vessels are the most accessible structures within a tumor mass and that a vigorous neo-vasculature development is a common feature of virtually all solid and hematologic malignancies. Vascular targeting antibodies functionalized with different payloads are currently being investigated in patients with solid tumors and are increasingly being considered also for the treatment of hematological malignancies. In the present work, we evaluated the efficacy of the fusion protein L19-IL2, comprising the human monoclonal antibody fragment scFv(L19) linked to the cytokine Interleukin-2 (IL-2), against Mantle Cell Lymphoma (MCL), a disease for which existing therapeutic approaches still remain highly unsatisfactory. Methods: Expression of the extra-domain B of fibronectin (EDB-Fn), a well-characterized marker of angiogenic blood vessels, was analyzed in Granta-519 and HBL-2 MCL xenografts and human MCL specimens using immunohistochemistry and dual-color immunofluorescence. The in vivo targeting performance of the EDB-Fn targeting immunocytokine L19-IL2 was investigated using ex vivo immunofluorescence analyses. SCID mice xenografted subcutaneously with Granta-519 or intravenously with HBL-2 MCL cells were used for mono- and combination therapy experiments, featuring i.v. injections of L19-IL2 (30 μg, corresponding to 9.9 μg or 177000 IU rIL-2 equivalents), unconjugated rIL-2 (9.9 μg), the anti-CD20 antibody rituximab (200 μg), rituximab plus IL-2, rituximab plus L19-IL2 or saline. Results: In vivo, L19-IL2 selectively homed to EDB-Fn expressing angiogenic blood vessels, thereby mediating the accumulation of IL-2 in MCL lesions. In mono-therapy experiments, L19-IL2 showed a superior anti-lymphoma activity compared to equimolar amounts of non-targeted recombinant IL-2. In combination with rituximab, L19-IL2 induced complete remissions (CR) of established subcutaneous Granta-519 tumors in 75 % (6/8) of the cases, whereas rituximab alone or in combination with free IL-2 only delayed lymphoma progression. Mice that experienced lymphoma relapse after having achieved a CR responded a second time to L19-IL2 and rituximab treatment. In the systemic HBL-2 MCL model, the combination of L19-IL2 and rituximab almost doubled survival of mice as compared to IL-2 and rituximab (median survival 63 vs. 33 days). Conclusions: In summary, we show that the vascular targeting immunocytokine L19-IL2 promotes a potent anti-lymphoma response in combination with anti-CD20 immunotherapy. The clinical evaluation of this combination is facilitated by the fact that L19-IL2 is entirely human and already being studied in Phase II clinical trials in patients with solid tumors. Disclosures: Menssen: Philogen: Employment. Neri:Philogen: Dario Neri is a co-founder and shareholder of Philogen, the biotech company which has licensed the L19 antibody from the ETH Zurich Other, Equity Ownership.

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Niglio, Scot Anthony, Daniel da Motta Girardi, Lisa M. Cordes, Lisa Ley, Marissa Mallek, Olena Sierra Ortiz, Jacqueline Cadena, et al. "A phase I study of bintrafusp alfa (M7824) and NHS-IL12 (M9241) alone and in combination with stereotactic body radiation therapy (SBRT) in adults with metastatic non-prostate genitourinary malignancies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS4599. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4599.

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TPS4599 Background: The majority of non- prostate genitourinary (GU) cancers are lethal when metastatic and rare GU cancers have limited treatment options. Bintrafusp alfa is a bifunctional fusion protein composed of human TGF-β receptor II, which sequesters or “traps” all three TGF-β isoforms and a monoclonal PD-L1 antibody. NHS-IL12 is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA) allowing for targeted delivery of pro-inflammatory cytokine, IL-12, to necrotic portions of tumor with DNA exposure to promote local immunomodulation. Preclinical data suggest synergy between these two agents. There is also evidence suggesting that stereotactic body radiation therapy (SBRT) can promote anti-tumor immune responses both locally and systemically while also synergizing with immune checkpoint inhibitors. Therefore, the combination of Bintrafusp alfa, NHS-IL12 and radiation is a potential strategy for metastatic non-prostate GU tumors. Methods: This is an open label, non-randomized, three-stage phase I trial of bintrafusp alfa and NHS-IL12 or bintrafusp alfa and NHS-IL12 in combination with either sequential or concurrent SBRT. Bintrafusp alfa (IV 1200 mg q2w) and SBRT (8 Gy x 3 fractions) are planned with a deescalating NHS-IL12 (subQ q4w) dose schedule. The accrual ceiling has been set at 66 patients. The trial will enroll patients with a pathologically confirmed diagnosis of metastatic non-prostate genitourinary cancer with an ECOG ≤ 2 (KPS ≥60%). Participants may have had prior cancer immunotherapy but excluding prior treatment with bintrafusp alfa and/or NHS-IL12. 9 patients will receive treatment in cycles consisting of 4 weeks. The primary objective is to determine the safety and highest tolerated doses with acceptable toxicity (recommended phase II dose) of bintrafusp alfa and NHS-IL12 alone or in combination with SBRT administered sequentially or concurrently in patients with metastatic non-prostate genitourinary cancers. Secondary objectives are objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Exploratory objectives are to determine peripheral immune modulation and the status of the immune microenvironment using cytokine analysis, circulating tumor cells, multiplex immunohistochemistry, T-cell receptor sequencing, and RNA-sequencing. The study is open and enrolling. Clinical trial information: NCT04235777.

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Berdel, Andrew F., Christoph Rollig, Martin Wermke, Linus Angenendt, Leo Ruhnke, Jan-Henrik Mikesch, Teresa Hemmerle, et al. "A Phase I Trial of the Antibody-Cytokine Fusion Protein F16IL2 in Combination with Anti-CD33 Immunotherapy for Posttransplant AML Relapse." Blood 138, Supplement 1 (November 5, 2021): 2345. http://dx.doi.org/10.1182/blood-2021-145859.

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Abstract Introduction Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but shortage of environmental growth factors and deficient recognition of malignant cells may limit their anticancer efficacy. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to the leukemia-modified extracellular matrix (ECM) would increase NK cell abundance and activity to potentiate antibody-dependent cellular cytotoxicity (ADCC) against acute myeloid leukemia (AML) blasts. In this novel-novel combination dose-escalation phase 1 trial, we enrolled patients with AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of F16IL2, an antibody-cytokine fusion protein composed of the human antibody fragment scFv(F16) in diabody format and two molecules of human IL-2, in combination with the Fc-optimized, ADCC-mediating anti-CD33 monoclonal antibody BI 836858. F16 specifically targets the A1 domain of the ECM protein tenascin C (TnC), which is spliced into the TnC molecule during active angiogenesis and tissue remodeling while it is virtually absent in normal tissues. Methods F16IL2 (10 - 20 Mio IU IV) was administered on days 1, 8, 15 and 22 of 28-day cycles, followed by administration of BI 836858 (10 - 40 mg IV) two days after each F16IL2 infusion. Dose escalation was performed over 4 dose levels (DL). Cohort 1 (10 Mio IU F16IL2 and 10 mg BI 836858, n = 5), cohort 2 (10 Mio IU F16IL2 and 20 mg BI 836858, n = 3), cohort 3 (20 Mio IU F16IL2 and 20 mg BI 836858, n = 4), cohort 4 (20 Mio IU F16IL2 and 40 mg BI 836858, n = 3). Safety and tolerability, pharmacodynamics and -kinetics, clinical efficacy and immune effector cell dynamics were investigated. This trial was registered at EudraCT as #2015-004763-37. Results Between December 2016 and March 2020, 15 patients with a median age of 50 years (range, 20 - 68) were enrolled and treated across 4 dose levels. Six patients (40%) had received two or more prior HSCT. The most frequent drug-related AEs (F16IL2 or BI 836858 or combination) were pyrexia (n = 13, 87%), chills (n = 12, 80%) and infusion-related reactions (n = 9, 60%), consistent with the expected toxicity profile of cytokine-armed or naked mAbs. These events were generally manageable, transient and of grade ≤ 2. One dose-limiting toxicity occurred at each of DL 3 (pulmonary edema) and 4 (acute GVHD). No patient died within the first 30 days of treatment initiation. Whereas no formal maximum tolerated dose (MTD) was reached, the maximum tested dose of 20 Mio IU F16IL2 and 40 mg BI 836858 was considered the recommended dose (RD). Three objective responses (1 CR, 1 CRi, 1 PR in extramedullary AML) were observed among 7 patients treated at the two higher DL, whereas no responses occurred at the two starting DL. Median OS among all 15 patients was 4.8 months (1.5 - 12.9), with a 6- and 12-month OS of 40% and 27%, respectively. Among those 7 patients whose AML was at least temporarily controlled with study treatment (CR/CRi, PR, SD), 12-month OS was 67% vs. 0% in non-responders. Combination therapy stimulated the expansion and activation of NK cells in bone marrow and peripheral blood. Conclusions To the best of our knowledge, this is the first study demonstrating that the strategy of potentiating ADCC with tumor-targeted immunocytokines is feasible in humans. In the difficult-to-treat situation of posttransplant AML relapse, responses were observed at higher DL, even in patients with extramedullary disease. The antibody-mediated targeted delivery of IL-2 to the ECM combined with anti-CD33 immunotherapy represents an innovative experimental approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. Disclosures Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Hemmerle: Philogen S.p.A.: Current Employment. Schäfers: Philogen S.p.A.: Research Funding. Rossig: BMS and Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; AdBoards by Amgen: Honoraria. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Rueter: Boehringer Ingelheim Pharma GmbH & Co. KG: Current Employment. Neri: Philogen S.p.A.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Multiple patents on vascular targeting; ETH Zurich: Patents & Royalties: CD117xCD3 TEA. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schliemann: Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Other: travel grants; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy, Other: travel grants.

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Pelegrin, Mireia, Laurent Gros, Hanna Dreja, and Marc Piechaczyk. "Monoclonal Antibody-based Genetic Immunotherapy." Current Gene Therapy 4, no. 3 (September 1, 2004): 347–56. http://dx.doi.org/10.2174/1566523043346246.

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Schuster, James M., and Darell D. Bigner. "Immunotherapy and monoclonal antibody therapies." Current Opinion in Oncology 4, no. 3 (June 1992): 547–52. http://dx.doi.org/10.1097/00001622-199206000-00020.

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Mehra, NarinderK. "Antibody therapy: Substitution-immunomodulation -monoclonal immunotherapy." Indian Journal of Medical Research 149, no. 4 (2019): 563. http://dx.doi.org/10.4103/ijmr.ijmr_2198_18.

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Miller, Brian J., and Peter F. Buckley. "Monoclonal antibody immunotherapy in psychiatric disorders." Lancet Psychiatry 4, no. 1 (January 2017): 13–15. http://dx.doi.org/10.1016/s2215-0366(16)30366-2.

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Hamblin, T. J. "Modifications of monoclonal antibody for immunotherapy." Transfusion Science 10, no. 1 (January 1989): 27–37. http://dx.doi.org/10.1016/0955-3886(89)90006-4.

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Imai, Kohzoh, Masato Hareyama, Yusuke Makiguchi, Hiroyuki Matsumoto, and Yuji Hinoda. "Monoclonal Antibody-Conjugated Immunotherapy of Cancer." International Reviews of Immunology 14, no. 2-3 (January 1997): 213–27. http://dx.doi.org/10.3109/08830189709116853.

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Danylesko, Ivetta, Katia Beider, Avichai Shimoni, and Arnon Nagler. "Monoclonal antibody-based immunotherapy for multiple myeloma." Immunotherapy 4, no. 9 (September 2012): 919–38. http://dx.doi.org/10.2217/imt.12.82.

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Stopforth, Richard J., Kirstie L. S. Cleary та Mark S. Cragg. "Regulation of Monoclonal Antibody Immunotherapy by FcγRIIB". Journal of Clinical Immunology 36, S1 (27 лютого 2016): 88–94. http://dx.doi.org/10.1007/s10875-016-0247-8.

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Hubert, Pascale, and Sebastian Amigorena. "Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy." OncoImmunology 1, no. 1 (January 2012): 103–5. http://dx.doi.org/10.4161/onci.1.1.17963.

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Johnson, Erik, Shannon M. Dean, and Paul M. Sondel. "Antibody-based immunotherapy in high-risk neuroblastoma." Expert Reviews in Molecular Medicine 9, no. 34 (December 2007): 1–21. http://dx.doi.org/10.1017/s1462399407000518.

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AbstractAlthough great advances have been made in the treatment of low- and intermediate-risk neuroblastoma in recent years, the prognosis for advanced disease remains poor. Therapies based on monoclonal antibodies that specifically target tumour cells have shown promise for treatment of high-risk neuroblastoma. This article reviews the use of monoclonal antibodies either as monotherapy or as part of a multifaceted treatment approach for advanced neuroblastoma, and explains how toxins, cytokines, radioactive isotopes or chemotherapeutic drugs can be conjugated to antibodies to enhance their effects. Tumour resistance, the development of blocking antibodies, and other problems hindering the effectiveness of monoclonal antibodies are also discussed. Future therapies under investigation in the area of immunotherapy for neuroblastoma are considered.

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Jefferis, Roy. "Monoclonal antibodies in immunotherapy." Journal of Prescribing Practice 1, no. 1 (January 2, 2019): 26–31. http://dx.doi.org/10.12968/jprp.2019.1.1.26.

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The bench-to-bedside ideal is being realised for both humoral and cellular immunotherapy. Monoclonal antibodies (mAbs) are established in the clinic, but continuous development has resulted in progression from mouse/human chimeric to humanised, ‘fully’ human, antibody–drug conjugates, biosimilars and biobetter therapeutics. The objective has been to minimise their potential for immunogenicity and to elucidate and exploit their multiple mechanisms of action (MoA). However, exploitation of these advances within the NHS is limited due their high cost. Consequently, the National Institute for Health and Care Excellence (NICE) offers evidence-based recommendations for the availability of approved mAbs, and other ‘speciality drugs’ within the NHS; alternative avenues for funding may be available while the efficacy of such drug is being fully evaluated. More cost-effective treatment is being achieved through patient stratification following genome sequencing and identification of polymorphisms that predispose people to disease susceptibilities and their responses to particular drugs or combinations of therapeutics.

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Siebert, Nikolai, Justus Leopold, Maxi Zumpe, Sascha Troschke-Meurer, Simon Biskupski, Alexander Zikoridse, and Holger N. Lode. "The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD2 Antibody Dinutuximab Beta." Cancers 14, no. 19 (October 4, 2022): 4842. http://dx.doi.org/10.3390/cancers14194842.

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Treatment of high-risk neuroblastoma (NB) patients with the anti-GD2 antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.

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Christiansen, Jason, and Ayyappan K. Rajasekaran. "Biological impediments to monoclonal antibody–based cancer immunotherapy." Molecular Cancer Therapeutics 3, no. 11 (November 1, 2004): 1493–501. http://dx.doi.org/10.1158/1535-7163.1493.3.11.

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Abstract The ability of antibodies to exploit antigenic differences between normal and malignant tissues and to exact a variety of antitumor responses offers significant advantages to conventional forms of therapy. Several monoclonal antibodies (mAb) have already proved to be relatively well tolerated and effective for the treatment of many different malignant diseases. However, mAbs must overcome substantial obstacles to reach antigens presented on target cells to be of therapeutic value. Intravenously administered antibodies must avoid host immune response and contend with low or heterogeneous expression of antigen on tumor cells. Antibodies must also overcome significant physical barriers en route to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers. Here we review the application and evolution of mAbs as effective forms of treatment, with particular attention to the barriers and impediments to successful treatment and discuss strategies to overcome these barriers and improve the efficacy of mAb-based therapy.

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21

Tempero, M. A., F. Haga, C. Sivinski, Z. Steplewski, H. D. Kay, and P. Pour. "Immunotherapy with Monoclonal Antibody (Mab) in Pancreatic Adenocarcinoma." International Journal of Pancreatology 9, no. 1 (June 1991): 125–34. http://dx.doi.org/10.1007/bf02925588.

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22

Taomoto, K., A. Ljichi, T. Sasayama, S. Matsumoto, and H. Hagiwara. "Immunotherapy for glioma patients with human monoclonal antibody." Clinical Neurology and Neurosurgery 99 (July 1997): S4. http://dx.doi.org/10.1016/s0303-8467(97)81256-5.

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23

Nessa, Meher Un, Md Atiar Rahman, and Yearul Kabir. "Plant-Produced Monoclonal Antibody as Immunotherapy for Cancer." BioMed Research International 2020 (August 25, 2020): 1–10. http://dx.doi.org/10.1155/2020/3038564.

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Plant-based products have expanded to include cancer immunotherapy, which has made great strides over recent years. Plants are considered inexpensive and facile production platforms for recombinant monoclonal antibody (mAb) due to the latest advancements and diversification of transgenic techniques. Current human biologics, including those based on mAbs produced by fermentation technologies using primarily mammalian cell cultures, have been replaced by plant-produced mAbs, which are cost effective, more scalable, speedy, versatile, and safer. Moreover, the use of animals for antibody production is always a question of ethical unambiguity, and the suitability of animal models for predicting the immunogenicity of therapeutic mAbs in humans and transposition of the immunogenic potential of therapeutic antibodies in animals to the human situation has no scientific rationale. Quite a few plant-based mAbs are approved for the treatment of cancer, ranging from tumors to hematological malignancies. This review focuses on the cutting-edge approaches for using plant-derived mAbs to suppress or prevent cancers. It also discusses the avenues taken to prevent infection by oncogenic viruses, solid tumors, lymphomas, and other cancerous conditions using mAbs. The review emphasizes the use of a plant-derived monoclonal antibody as a premier platform to combat cancer.

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Rossi, Edmund A., David M. Goldenberg, Thomas M. Cardillo, Rhona Stein та Chien-Hsing Chang. "CD20-targeted tetrameric interferon-α, a novel and potent immunocytokine for the therapy of B-cell lymphomas". Blood 114, № 18 (29 жовтня 2009): 3864–71. http://dx.doi.org/10.1182/blood-2009-06-228890.

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Abstract Interferon-α (IFN-α) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. A tumor-targeting antibody-IFN-α conjugate (mAb-IFN-α) could kill by direct actions of the monoclonal antibody (mAb) and IFN-α on tumor cells and also potentiate a tumor-directed immune response. The modular Dock-and-Lock method (DNL) was used to generate 20-2b, the first immunocytokine having 4 cytokine (IFN-α2b) groups that are fused to the humanized anti-CD20 mAb, veltuzumab. Additional mAb-IFN-α constructs, each retaining potent IFN-α2b biologic activity, also were produced by DNL. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-α. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN-α in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-α2b. Targeting IFN-α with an anti-CD20 mAb makes the immunocytokine more potent than either agent alone. These findings suggest that 20-2b merits clinical evaluation as a new candidate antilymphoma therapeutic.

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Crescioli, Silvia, Ann L. White, and Sophia N. Karagiannis. "Special Issue “Antibody Engineering for Cancer Immunotherapy”." Antibodies 11, no. 2 (April 15, 2022): 29. http://dx.doi.org/10.3390/antib11020029.

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Since the approval of Rituximab in the late 1990s, the first chimeric monoclonal antibody for the treatment of non-Hodgkin lymphoma, antibody engineering for cancer immunotherapy has become a rapidly growing field, with almost 50 antibody therapeutics approved in the USA and EU and hundreds undergoing testing in clinical trials [...]

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26

Gajdosik, Z. "Monalizumab. Anti-NKG2A monoclonal antibody, Checkpoint inhibitor, Cancer immunotherapy." Drugs of the Future 44, no. 9 (2019): 699. http://dx.doi.org/10.1358/dof.2019.44.9.3035582.

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Kelly, Timothy M., Peter Thomas, and Aniruddha Ganguly. "Experimental Immunotherapy of Colorectal Carcinoma by Monoclonal Antibody ND4." Hybridoma 26, no. 1 (February 2007): 10–16. http://dx.doi.org/10.1089/hyb.2006.036.

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Miller, Brian J., and Peter F. Buckley. "The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia." Psychiatric Clinics of North America 39, no. 2 (June 2016): 187–98. http://dx.doi.org/10.1016/j.psc.2016.01.003.

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29

Essali, Norah, David R. Goldsmith, Laura Carbone, and Brian J. Miller. "Psychosis as an adverse effect of monoclonal antibody immunotherapy." Brain, Behavior, and Immunity 81 (October 2019): 646–49. http://dx.doi.org/10.1016/j.bbi.2019.06.002.

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30

Schulz, G., M. Büchler, K. H. Muhrer, R. Klapdor, R. Kübel, H. P. Harthus, N. Madry, and K. Bosslet. "Immunotherapy of pancreatic cancer with monoclonal antibody BW 494." International Journal of Cancer 41, S2 (1988): 89–94. http://dx.doi.org/10.1002/ijc.2910410721.

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Rahman, M. Ashikur, Fargana Islam, Mahedi Hasan, Irin S. Joya, Maisha M. Mithila, M. Fahim Islam, and M. Rashedur Rahman. "Monoclonal antibody: a cell specific immunotherapy to treat cancer." International Journal of Basic & Clinical Pharmacology 12, no. 2 (February 22, 2023): 290–302. http://dx.doi.org/10.18203/2319-2003.ijbcp20230404.

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Fundamentally, the therapy technique which is utilized in malignancy immunotherapy, monoclonal antibodies (mAb), is one of them, and it is used extensively as a treatment for the disease. To achieve more successful treatment, novel combination treatments and treatment procedures must be created. The purpose of this study is the improvement of mAb treatment and detail late advance and new limits, particularly in cancer therapy. With various keywords, we searched Google Scholar, PubMed, and Scopus for monoclonal antibody therapy as an alternate form of chemotherapy. The number of patients who received each therapy regimen, and the recovery rate are all displayed in this study, also a comparative study between monotherapy and chemotherapy. The result showed that rituximab had a greater overall response rate than other drugs, at 68%. In the combination treatment group (monotherapy+chemotherapy), 100% of patients had adverse events, compared to 84.2 percent in the monotherapy group. The pharmaceutical industry's fastest-growing medications, monoclonal antibodies are increasingly being examined in Clinical trials as stand-alone treatments or in conjunction with other therapies. It has a promising future since it will provide better tailored therapy and combination therapy for the treatment of cancer.

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Tuladhar, Reshma. "Implication of Monoclonal Antibody for COVID-19 Treatment." Journal of Institute of Science and Technology 25, no. 2 (December 25, 2020): 133–40. http://dx.doi.org/10.3126/jist.v25i2.33750.

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Coronavirus induced disease-19 (COVID-19) pandemic affecting the entire world has continued to pose threat despite nearly a year of its onset. With more than 50 vaccine candidates targeting COVID-19 on trials and 15 at the final stage of testing, wide availability to the general public is still a long way to go. Thus alternative therapeutics is in the progress to minimize the effect of COVID-19. This systematic review evaluated the articles related to immunotherapy for COVID19. PubMed database was used to search for keywords; COVID-19, immunotherapy, and monoclonal antibody for relevant publications of the year 2020. The review was performed based on PRISMA protocol and the final 20 articles were included in the final review. These studies demonstrated that Tocilizumab, the monoclonal antibody that blocks IL6 receptors has improved outcomes in COVID-19 infected patients.

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Cabello-Alemán, Lucía. "Future directions in cancer immunotherapy with monoclonal antibodies." Research Results in Pharmacology 8, no. 4 (December 15, 2022): 101–7. http://dx.doi.org/10.3897/rrpharmacology.8.85918.

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Introduction: Cancer immunotherapy with monoclonal antibodies (mAbs) has become a therapy with great potential nowadays. It is based on the affinity of antibodies to bind to specific molecules, thus inhibiting the growth and spread of cancer. There is a wide variety of mAbs with differentiated mechanisms and enormous clinical benefits. However, different immunotherapeutic alternatives have emerged due to their limitations, such as the long duration of organ toxicity and the inability to penetrate intracellularly. This mini-review will discuss the emerging alternatives of cancer immunotherapies based on mAbs. Bispecific antibodies (BsAbs): Antibodies designed to bind to two epitopes of an antigen. Antibody fragments: Fragments of the Fab region generated from the variable region of IgG and IgM and a scFv. Antibody-drug conjugates (ADCs): Administration of mAbs and a toxin of high specificity for a tumour target. Nanobodies (or nanocomponents): Small fragments of antibody heavy chain. Intrabodies (or intracellular antibodies): Antibodies that are expressed intracellularly and synthesised inside cells by retroviral delivery systems. Stereospecific and catalytic mAbs: Antibodies that recognise the 3D configurations of target molecules. Combination immunotherapies: Therapies that combine cytokines with tumour-targeted mAbs. Small molecule immunotherapeutics: Small molecule drugs that can stimulate intracellular pathways primarily involved in immune cell checkpoints and bind to mAb-like targets. Conclusion: These new varieties of immunotherapy present significant advantages, but future research should continue to improve their efficacy and safety and identify new biomarkers. Graphical abstract:

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34

Schliemann, Christoph, Alessandro Palumbo, Kathrin Zuberbühler, Alessandra Villa, Manuela Kaspar, Eveline Trachsel, Wolfram Klapper, Hans Dietrich Menssen, and Dario Neri. "Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2." Blood 113, no. 10 (March 5, 2009): 2275–83. http://dx.doi.org/10.1182/blood-2008-05-160747.

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Abstract The antibody-mediated delivery of therapeutic agents to sites of angiogenesis is an attractive strategy for anticancer therapy, but is largely unexplored in hematologic malignancies. In the present study, we show that the extra domain B (EDB) of fibronectin, a marker of angiogenesis, is expressed in B-cell non-Hodgkin lymphoma (NHL) and that the human monoclonal anti-EDB antibody L19 can selectively localize to the lymphoma-associated subendothelial extracellular matrix. In vivo, the preferential accumulation of the antibody at the tumor site was confirmed by quantitative biodistribution analyses with radioiodinated antibody preparations. The fusion protein L19-IL2, which mediates the delivery of interleukin-2 (IL-2) to the neovasculature, displayed a superior antilymphoma activity compared with unconjugated IL-2 in localized and systemic xenograft models of NHL. When coadministered with rituximab, L19-IL2 induced complete remissions of established localized lymphomas and provided long-lasting protection from disseminated lymphoma. The combined use of rituximab and L19-IL2, which dramatically increases the infiltration of immune effector cells in lymphomas, may deserve clinical investigations, facilitated by the fact that L19-IL2 is currently being studied in phase II clinical trials in patients with solid tumors.

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Qiao, Jingbo, Junquan Liu, Jillian C. Jacobson, Rachael A. Clark, Sora Lee, Li Liu, Zhiqiang An, Ningyan Zhang, and Dai H. Chung. "Anti-GRP-R monoclonal antibody antitumor therapy against neuroblastoma." PLOS ONE 17, no. 12 (December 16, 2022): e0277956. http://dx.doi.org/10.1371/journal.pone.0277956.

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Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.

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Moussavou, Ghislain, Kisung Ko, Jeong-Hwan Lee, and Young-Kug Choo. "Production of Monoclonal Antibodies in Plants for Cancer Immunotherapy." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/306164.

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Plants are considered as an alternative platform for recombinant monoclonal antibody (mAb) production due to the improvement and diversification of transgenic techniques. The diversity of plant species offers a multitude of possibilities for the valorization of genetic resources. Moreover, plants can be propagated indefinitely, providing cheap biomass production on a large scale in controlled conditions. Thus, recent studies have shown the successful development of plant systems for the production of mAbs for cancer immunotherapy. However, their several limitations have to be resolved for efficient antibody production in plants.

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Szymański, Wojciech, Agnieszka Gornowicz, Anna Bielawska, and Krzysztof Bielawski. "The application of nanotechnology in cancer immunotherapy." Postępy Higieny i Medycyny Doświadczalnej 74 (May 22, 2020): 131–43. http://dx.doi.org/10.5604/01.3001.0014.1527.

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Targeted therapy is associated with the use of drugs designed against specific molecular targets. Their mechanism of action is based on the inhibition of specific signaling pathways in processes related to the development of cancer (proliferation, invasion, angiogenesis or metastasis). One of the most important methods of treatment is immunotherapy, which uses monoclonal antibodies. Their mechanism of action is based on inducing programmed cell death by inhibiting specific signal transduction processes. However, immunotherapy has a number of limitations, including side effects that may endanger the patient’s life. To overcome those obstacles immunoconjugates were developed, which combine a monoclonal antibody, or its fragment, with a drug using a stable linker. Their mechanism of action is based on the monoclonal antibody binding to a cell membrane receptor, their internalization, the degradation of the linker, and the release of the drug attached to the antibody, which then activates specific genes or proteins or induces apoptosis. Immunoconjugates represent a promising alternative for anticancer treatment used today, but their use is associated with some obstacles. Nanotechnology helps to solve these problems with a chemotherapeutics delivery system called immunonanoparticles. It uses chemotherapeutics encapsulated in nanoparticles in combination with monoclonal antibodies displaying the ability of selective recognition and binding with molecular targets on the surface of selected cancer cells. This review focuses on presenting the most important solutions used in targeted therapy, which combine traditional immunotherapy with modern nanotechnology.

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38

Tan, Guang-Hong. "Immunotherapy of hepatoma with a monoclonal antibody against murine endoglin." World Journal of Gastroenterology 13, no. 17 (2007): 2479. http://dx.doi.org/10.3748/wjg.v13.i17.2479.

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39

Cheng, Jonathan D., Paula T. Rieger, Margaret von Mehren, Gregory P. Adams, and Louis M. Weiner. "Recent advances in immunotherapy and monoclonal antibody treatment of cancer." Seminars in Oncology Nursing 16 (November 2000): 2–12. http://dx.doi.org/10.1053/sonu.2000.19775.

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40

Zhang, Hongyu, Mi Deng, Fen Pei, Shouye Wang, and Mitchell Ho. "Next-Generation Antibody Therapeutics: Discovery, Development and Beyond: highlights of the third annual conference of the Chinese Antibody Society." Antibody Therapeutics 2, no. 4 (October 1, 2019): 99–107. http://dx.doi.org/10.1093/abt/tbz012.

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ABSTRACT The Chinese Antibody Society (CAS) convened the third annual conference in Cambridge, Massachusetts, USA on April 7, 2019. More than 600 global members attended the meeting. The theme of this conference was Next-Generation Antibody Therapeutics: Discovery, Development and Beyond. The meeting covered a vast variety of topics including cancer immunotherapy, single-domain antibodies as well as bispecific antibodies, immunotoxins, transgenic mouse platforms for next-generation monoclonal antibody discovery and antibody chemistry, manufacturing and controls (CMCs). Two hot topics were comprehensively discussed by the prestigious panelists and hosts at the panel discussions during the conferences, i.e., bispecific antibodies and antibody CMC. Statement of Significance: The Chinese Antibody Society convened the third annual conference in Cambridge, Massachusetts, USA on 7 April 2019. The meeting covered a variety of topics, including cancer immunotherapy, single-domain antibody, bispecific antibody, immunotoxin, transgenic mouse platforms for next-generation monoclonal antibody discovery and antibody CMC.

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May, Kenneth F., Bettina Franz, Christopher Harvey, F. Stephen Hodi, Glenn Dranoff, and Kai Wucherpfennig. "Isolation of human anti-MICA antibody from cancer patients responding to immunotherapies." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 2502. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2502.

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2502 Background: Immunotherapy is a promising modality for the treatment of cancer, and elucidating the mechanism of action is crucial to guiding patient selection and developing future immunotherapeutic strategies. Engagement of the immune molecule NKG2D by the cancer antigen MICA is important for immune surveillance of many cancers. Tumors can evade immune surveillance by shedding cell surface MICA, which leads to dampening of anti-tumor immunity. Investigations by our laboratory revealed that patients responding to immunotherapy can mount antibody responses targeting MICA, which permits re-engagement of immunity. Methods: Patients with advanced cancer treated at our institution with immunotherapies (tumor cell vaccination, ipilimumab) were identified, including several with long-term clinical remissions. Plasma was analyzed for MICA reactivity to three distinct MICA alleles, and rare memory B cells reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin heavy and light chain variable domains were sequenced with single cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma from patients treated with immunotherapy revealed considerable inter-patient variation in reactivity to MICA. Patients with marked plasma reactivity (including several with sustained clinical remissions) were selected for isolation of rare memory B cells reactive to MICA. From these cells, we have generated a recombinant fully-human MICA-reactive monoclonal antibody that exhibits binding to a variety of MICA alleles. Conclusions: We have developed novel methods to analyze anti-MICA antibody responses and isolate rare memory B cells from cancer patients who gained significant clinical benefit from immunotherapy. This has facilitated the generation of fully human recombinant anti-MICA monoclonal antibody. To our knowledge, this is the first example of a specific antibody reactive to a cancer antigen isolated from a cancer patient responding to immunotherapy. As these antibody responses likely played a role in tumor destruction, these results inform the development of new antibody-based immunotherapies targeting the NKG2D-MICA pathway.

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van Geel, Remon, and Floris van Delft. "Abstract 5606: GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5606. http://dx.doi.org/10.1158/1538-7445.am2022-5606.

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Abstract Engagement of T cell or NK cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-IL-15 immunocytokines, based on a variety of molecular architectures, are currently finding their way to the clinic with promising results. Here we demonstrate how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan, can be applied for attachment of IL-15 without prior antibody engineering. The molecular architecture of the resulting immune cell engagers (ICEs) can be readily tailored to 2:2 or 2:1 ratio (anti-TAA:IL-15) to mitigate cytokine release syndrome. Moreover, we show how immunostimulatory activity can be regulated via linker design, either by tailoring of IL-15-antibody spacing or by generation of a conditionally active IL-15 format. Structural and functional studies will be presented to corroborate the architecture of these GC™-ICEs and in vitro and in vivo activity in a syngeneic mouse model. Citation Format: Remon van Geel, Floris van Delft. GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy [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 5606.

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Kumar, Mohit, Chellappagounder Thangavel, Richard C. Becker, and Sakthivel Sadayappan. "Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity." Cancers 13, no. 1 (December 30, 2020): 86. http://dx.doi.org/10.3390/cancers13010086.

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Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

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Tai, Yu-Tzu, Patrick A. Mayes, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Jenny Craigen, et al. "Novel anti–B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma." Blood 123, no. 20 (May 15, 2014): 3128–38. http://dx.doi.org/10.1182/blood-2013-10-535088.

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Key Points Selective myeloma cell killing and enhanced effector function of a novel anti-BCMA antibody conjugated with MMAF via noncleavable linker. Specific multiple myeloma antigen for monoclonal antibody-based immunotherapy.

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45

Rybchenko, Vladislav S., Teimur K. Aliev, Anna A. Panina, Mikhail P. Kirpichnikov, and Dmitry A. Dolgikh. "Targeted Cytokine Delivery for Cancer Treatment: Engineering and Biological Effects." Pharmaceutics 15, no. 2 (January 19, 2023): 336. http://dx.doi.org/10.3390/pharmaceutics15020336.

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Anti-tumor properties of several cytokines have already been investigated in multiple experiments and clinical trials. However, those studies evidenced substantial toxicities, even at low cytokine doses, and the lack of tumor specificity. These factors significantly limit clinical applications. Due to their high specificity and affinity, tumor-specific monoclonal antibodies or their antigen-binding fragments are capable of delivering fused cytokines to tumors and, therefore, of decreasing the number and severity of side effects, as well as of enhancing the therapeutic index. The present review surveys the actual antibody–cytokine fusion protein (immunocytokine) formats, their targets, mechanisms of action, and anti-tumor and other biological effects. Special attention is paid to the formats designed to prevent the off-target cytokine–receptor interactions, potentially inducing side effects. Here, we describe preclinical and clinical data and the efficacy of the antibody-mediated cytokine delivery approach, either as a single therapy or in combination with other agents.

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Zahavi, David, Dalal AlDeghaither, Allison O’Connell, and Louis M. Weiner. "Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy." Antibody Therapeutics 1, no. 1 (June 2018): 7–12. http://dx.doi.org/10.1093/abt/tby002.

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ABSTRACT The targeting of surface antigens expressed on tumor cells by monoclonal antibodies (mAbs) has revolutionized cancer therapeutics. One mechanism of action of antibody-based immunotherapy is the activation of immune effector cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This review will summarize the process of ADCC, its important role in the efficacy of mAb therapy, how to measure it, and finally future strategies for antibody design that can take advantage of it to improve clinical performance.

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Song, Qing. "Microsystem enabled single cell monoclonal antibody cloning for antibody immunotherapy of HIV infection (features)." Global Vaccines and Immunology 1, no. 2 (2016): 24–28. http://dx.doi.org/10.15761/gvi.1000107.

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Tamura, Hideto, Mariko Ishibashi, Mika Sunakawa, and Koiti Inokuchi. "Immunotherapy for Multiple Myeloma." Cancers 11, no. 12 (December 12, 2019): 2009. http://dx.doi.org/10.3390/cancers11122009.

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Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

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Press, Oliver W., John P. Leonard, Bertrand Coiffier, Ronald Levy, and John Timmerman. "Immunotherapy of Non-Hodgkin's Lymphomas." Hematology 2001, no. 1 (January 1, 2001): 221–40. http://dx.doi.org/10.1182/asheducation-2001.1.221.

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Abstract Recent years have witnessed the development of a variety of promising immunotherapies for treating patients with non-Hodgkin's lymphomas. Foremost among these advances is the exciting success of monoclonal antibodies directed against lymphocyte surface antigens. Rituximab is a chimeric (human-mouse) anti-CD20 antibody that induces responses in approximately half of the patients with relapsed indolent lymphomas and a third of patients with relapsed aggressive lymphomas when used as a single agent. Response rates appear even higher (up to 70%) for newly diagnosed patients treated with Rituximab monotherapy. Other promising antibodies for treatment of B cell malignancies include epratuzumab (anti-CD22), CAMPATH-1H (anti-CD52w), and Hu1D10 (anti-class II HLA). Even more exciting than antibody monotherapy is the prospect of combination antibody therapy (e.g. rituximab + epratuzumab) or combination chemotherapy and antibody therapy. In this regard, a recent phase III randomized trial from the GELA group in France demonstrated statistically significantly superior complete and overall response rates and superior event-free and overall survivals for elderly patients with newly diagnosed diffuse aggressive B cell lymphomas treated with CHOP + rituximab compared with CHOP alone. Confirmatory cooperative group trials combining chemotherapy with antibody therapies are currently underway. Another approach to augment the efficacy of antibodies is to deploy them in radiolabeled form. Iodine-131, Yttrium-90, and Copper-67 labeled monoclonal antibodies targeting CD-20, CD-22, HLA class II, and other cell surface antigens have been tested and demonstrate higher overall response rates (50-80%) and complete response rates (20-40%) than unlabeled antibodies. Pilot studies combining radiolabeled antibodies with either standard dose chemotherapy or myeloablative chemoradiotherapy with stem cell transplantation also appear very promising. Lymphoma vaccines have also produced very encouraging results in single institution studies at Stanford and the National Cancer Institute, with responding patients demonstrating superior event-free and overall survival than historical controls. Phase III randomized trials of idiotype vaccines are currently underway and novel new vaccine approaches are also being tested.

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Zahavi, David, and Louis Weiner. "Monoclonal Antibodies in Cancer Therapy." Antibodies 9, no. 3 (July 20, 2020): 34. http://dx.doi.org/10.3390/antib9030034.

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Monoclonal antibody-based immunotherapy is now considered to be a main component of cancer therapy, alongside surgery, radiation, and chemotherapy. Monoclonal antibodies possess a diverse set of clinically relevant mechanisms of action. In addition, antibodies can directly target tumor cells while simultaneously promoting the induction of long-lasting anti-tumor immune responses. The multifaceted properties of antibodies as a therapeutic platform have led to the development of new cancer treatment strategies that will have major impacts on cancer care. This review focuses on the known mechanisms of action, current clinical applications for the treatment of cancer, and mechanisms of resistance of monoclonal antibody therapy. We further discuss how monoclonal antibody-based strategies have moved towards enhancing anti-tumor immune responses by targeting immune cells instead of tumor antigens as well as some of the current combination therapies.

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