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1
Esteva, Francisco J., Kathy D. Miller e Beverly A. Teicher. "What Can We Learn about Antibody-Drug Conjugates from the T-DM1 Experience?" American Society of Clinical Oncology Educational Book, n. 35 (maggio 2015): e117-e125. http://dx.doi.org/10.14694/edbook_am.2015.35.e117.
Testo completoAbstract (sommario):
Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation. Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment–protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates, and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40 antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for patients with cancer.
2
Ahmad, Ateeq, e Kevin Law. "Strategies for designing antibody-toxin conjugates". Trends in Biotechnology 6, n. 10 (ottobre 1988): 246–51. http://dx.doi.org/10.1016/0167-7799(88)90056-x.
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Govindan, Serengulam V., e David M. Goldenberg. "New Antibody Conjugates in Cancer Therapy". Scientific World JOURNAL 10 (2010): 2070–89. http://dx.doi.org/10.1100/tsw.2010.191.
Testo completoAbstract (sommario):
Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb,90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions.
4
Liang, X. P., M. E. Lamm e J. G. Nedrud. "Oral administration of cholera toxin-Sendai virus conjugate potentiates gut and respiratory immunity against Sendai virus." Journal of Immunology 141, n. 5 (1 settembre 1988): 1495–501. http://dx.doi.org/10.4049/jimmunol.141.5.1495.
Testo completoAbstract (sommario):
Abstract Successful oral immunization to prevent infectious diseases in the gastrointestinal tract as well as distant mucosal tissues may depend on the effectiveness of an Ag to induce gut immune responses. We and others have previously reported that cholera toxin possesses strong adjuvant effects on the gut immune response to co-administered Ag. To explore further adjuvant effects of cholera toxin, the holotoxin or its B subunit was chemically cross-linked to Sendai virus. The resulting conjugates, which were not infectious, were evaluated for their capacity to induce gut immune responses against Sendai virus after oral administration to mice. Conjugating cholera toxin to virus significantly enhanced the adjuvant activity of cholera toxin compared to simple mixing. Cholera toxin B subunit, however, did not show an adjuvant effect either by itself or conjugated with the virus. Oral administration of the Sendai virus-cholera toxin conjugate was also able to prime for protective anti-viral responses in the respiratory tract. Mice that were orally immunized with the conjugate and intra-nasally boosted with inactivated virus alone showed virus-specific IgA titers in nasal secretions that correlated with protection against direct nasal challenge with live Sendai virus. For comparison, s.c. immunization was also studied. Systemic immunization with the virus-cholera toxin conjugate induced virus-specific antibody responses in serum as well as in the respiratory tract but failed to protect the upper respiratory tract against virus challenge. Systemic immunization plus an intra-nasal boost did, however, confer a variable degree of protection to the upper respiratory tract, which correlated primarily with bronchoalveolar lavage (lung) antibody titers.
5
Panjideh, Hossein, Nicole Niesler, Alexander Weng e Hendrik Fuchs. "Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861". Toxins 14, n. 7 (13 luglio 2022): 478. http://dx.doi.org/10.3390/toxins14070478.
Testo completoAbstract (sommario):
Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia.
6
Faria, Morse, Marlking Peay, Brandon Lam, Eric Ma, Moucun Yuan, Michael Waldron, William Mylott, Meina Liang e Anton Rosenbaum. "Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276, an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2". Antibodies 8, n. 1 (11 gennaio 2019): 11. http://dx.doi.org/10.3390/antib8010011.
Testo completoAbstract (sommario):
Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: Total Antibody, Antibody Conjugated Toxin or Total ADC and Unconjugated Toxin. MEDI4276 is an ADC comprised of biparatopic humanized antibody attached via a protease-cleavable peptide-based maleimidocaproyl linker to a tubulysin toxin (AZ13599185) with an approximate average drug-antibody ratio of 4. The conjugated payload of MEDI4276 can undergo ester hydrolysis to produce the conjugated payload AZ13687308, leading to the formation of MEDI1498 (de-acetylated MEDI4276). In this report, we describe the development, validation and application of three novel multiplex bioanalytical methods. The first ligand-binding liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) method was developed and validated for simultaneous measurement of total antibody and total ADC (antibody-conjugated AZ13599185) from MEDI4276. The second LBA-LC-MS/MS assay quantified total ADC (antibody-conjugated AZ13687308) from MEDI1498. The third multiplex LC-MS/MS assay was used for simultaneous quantification of unconjugated AZ13599185 and AZ13687308. Additional stability experiments confirmed that quantification of the released warhead in the presence of high concentrations of MEDI4276 was acceptable. Subsequently, the assays were employed in support of a first-in-human clinical trial (NCT02576548).
7
Yu, Rui, Junjie Xu, Tao Hu e Wei Chen. "The Pneumococcal Polysaccharide-Tetanus Toxin Native C-Fragment Conjugate Vaccine: The Carrier Effect and Immunogenicity". Mediators of Inflammation 2020 (4 luglio 2020): 1–11. http://dx.doi.org/10.1155/2020/9596129.
Testo completoAbstract (sommario):
The encapsulated bacteria, as Streptococcus pneumonia, Haemophilus influenzae type b, and Neisseria meningitidis, cause serious morbidity and mortality worldwide. The capsular polysaccharide (PS), which could elicit a weak T cell-independent immune response, is a vital virulence determinant. One of the strategies to improve the PS-specific immunogenicity is to conjugate PS with a nontoxic carrier protein. Tetanus toxoid (TT) and CRM197 are the typical carrier proteins for the PS conjugate vaccines. TT is the inactivated tetanus toxin manipulated with formaldehyde, which suffers from the pollution from residual formaldehyde and the incomplete detoxification. CRM197 has the disadvantage of low-yield purification with the requirement of sophisticated culture conditions. Thus, a novel carrier protein without these disadvantages is highly required. The tetanus toxin native C-fragment (Hc) is safe, low-cost, and highly immunogenic with easy purification, which can act as a promising carrier protein. Pneumococcal serogroups 14 and 23F were major epidemic causes of pneumococcal infections. In the present study, the capsular PSs (PS14 and PS23F) were conjugated with Hc, TT, and CRM197, respectively. TT- and CRM197-based conjugates acted as controls for Hc-based conjugates (PS14-Hc and PS23F-Hc). The structural properties of Hc were not fundamentally changed after conjugated with PS. PS14-Hc and PS23F-Hc could potentiate sound PS-specific antibody levels comparable to the controls. Thus, Hc exhibited a practical carrier effect to help the pneumococcal conjugate vaccines perform good immunogenicities.
8
Marsh, J. W., e D. M. Neville. "A flexible peptide spacer increases the efficacy of holoricin anti-T cell immunotoxins." Journal of Immunology 140, n. 10 (15 maggio 1988): 3674–78. http://dx.doi.org/10.4049/jimmunol.140.10.3674.
Testo completoAbstract (sommario):
Abstract Immunotoxins, constructed by chemically cross-linking an antibody and protein toxin, do not possess the high efficacy of the native toxin. Decreases in toxicity are due in part to the steric constraints imposed on the two macromolecules, which result in both decreased antibody binding and toxin function. In examining the structural features that influence efficacy in holotoxin-antibody conjugates, it was found that the incorporation of a 29-residue polypeptide, derived from the insulin B chain between the antibody and ricin moiety, resulted in an increase in both potency and efficacy. In a murine model system, potency of the peptide spacer conjugate was increased nearly 10-fold; however, when examined by the procedure used to purge bone marrow, the peptide spacer conjugate was not demonstrably more toxic to nontarget cells than the nonspacer conjugate. Thus, in addition to increases of efficacy and potency, this novel immunotoxin demonstrated increased specificity by approximately 10-fold. To test the general utility of peptide spacer inclusion, a T101-ricin conjugate was constructed with the peptide spacer. It yielded a protein synthesis inhibition rate of -0.6 log/h on MOLT-3 cells, greater than 10-fold more efficacious than a previously constructed nonspacer T101-ricin conjugate examined under similar conditions.
9
Govindan, Serengulam V., Gary L. Griffiths, Hans J. Hansen, Ivan D. Horak e David M. Goldenberg. "Cancer Therapy with Radiolabeled and Drug/Toxin-conjugated Antibodies". Technology in Cancer Research & Treatment 4, n. 4 (agosto 2005): 375–91. http://dx.doi.org/10.1177/153303460500400406.
Testo completoAbstract (sommario):
Radioimmunotherapy and antibody-directed chemotherapy have emerged as cancer treatment modalities with the regulatory approval of products for non-Hodgkin's lymphoma and acute myeloid leukemia. Antibody-toxin therapy is likewise on the verge of clinical fruition. Accumulating evidence suggests that radioimmunotherapy may have the best impact in minimal-disease and adjuvant settings, especially with radioresistant solid tumors. For the latter, ongoing efforts in ‘pretargeting’ to increase deliverable tumor radiation dose, combination therapies, and locoregional applications are also of importance. Antibody-drug conjugates have the potential to increase the therapeutic index of chemotherapy by minimizing systemic toxicity and improving tumor targeting. The design of optimal drug conjugates in this regard is predicated upon the proper choice of the target antigen, the cleavable-linker, and the drug. In respect of antibody-toxin conjugates, considerable progress has been made in chemical and recombinant immunotoxin designs, and in the advancement of many products to clinical trials. Continued development of antibody-directed therapies should expand the options available for the management of cancer.
10
Lefeber, Dirk J., Barry Benaissa-Trouw, Johannes F. G. Vliegenthart, Johannis P. Kamerling, Wouter T. M. Jansen, Kees Kraaijeveld e Harm Snippe. "Th1-Directing Adjuvants Increase the Immunogenicity of Oligosaccharide-Protein Conjugate Vaccines Related to Streptococcus pneumoniae Type 3". Infection and Immunity 71, n. 12 (dicembre 2003): 6915–20. http://dx.doi.org/10.1128/iai.71.12.6915-6920.2003.
Testo completoAbstract (sommario):
ABSTRACT Oligosaccharide (OS)-protein conjugates are promising candidate vaccinesagainst encapsulated bacteria, such as Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. Although the effects of several variables such as OS chain length and protein carrier have been studied, little is known about the influence of adjuvants on the immunogenicity of OS-protein conjugates. In this study, a minimal protective trisaccharide epitope of Streptococcus pneumoniae type 3 conjugated to the cross-reacting material of diphtheria toxin was used for immunization of BALB/c mice in the presence of different adjuvants. Subsequently, half of the mice received a booster immunization with conjugate alone. Independent of the use and type of adjuvant, all mice produced long-lasting anti-polysaccharide type 3 (PS3) antibody levels, which provided full protection against challenge with pneumococcal type 3 bacteria. All adjuvants tested increased the anti-PS3 antibody levels and opsonic capacities as measured by an enzyme-linked immunosorbent assay and an in vitro phagocytosis assay. The use of QuilA or a combination of the adjuvants CpG and dimethyl dioctadecyl ammonium bromide resulted in the highest phagocytic capacities and the highest levels of Th1-related immunoglobulin G (IgG) subclasses. Phagocytic capacity correlated strongly with Th1-associated IgG2a and IgG2b levels, to a lesser extent with Th2-associated IgG1 levels, and weakly with thiocyanate elution as a measure of avidity. Thus, the improved immunogenicity of OS-protein conjugates was most pronounced for Th1-directing adjuvants.
11
Messerschmidt, Katrin, e Katja Heilmann. "Toxin–antigen conjugates as selection tools for antibody producing cells". Journal of Immunological Methods 387, n. 1-2 (gennaio 2013): 167–72. http://dx.doi.org/10.1016/j.jim.2012.10.010.
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ARNDT, R., e H. J. THIESEN. "Elimination of Trinitrophenol-Specific Antibody Response by Antigen-Toxin Conjugates". Scandinavian Journal of Immunology 22, n. 5 (novembre 1985): 489–94. http://dx.doi.org/10.1111/j.1365-3083.1985.tb01907.x.
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Ou, Li, Krishana Gulla, Andrea Biju, Daniel W. Biner, Tatsiana Bylund, Anita Changela, Steven J. Chen et al. "Assessment of Crosslinkers between Peptide Antigen and Carrier Protein for Fusion Peptide-Directed Vaccines against HIV-1". Vaccines 10, n. 11 (12 novembre 2022): 1916. http://dx.doi.org/10.3390/vaccines10111916.
Testo completoAbstract (sommario):
Conjugate-vaccine immunogens require three components: a carrier protein, an antigen, and a crosslinker, capable of coupling antigen to carrier protein, while preserving both T-cell responses from carrier protein and B-cell responses from antigen. We previously showed that the N-terminal eight residues of the HIV-1 fusion peptide (FP8) as an antigen could prime for broad cross-clade neutralizing responses, that recombinant heavy chain of tetanus toxin (rTTHC) as a carrier protein provided optimal responses, and that choice of crosslinker could impact both antigenicity and immunogenicity. Here, we delve more deeply into the impact of varying the linker between FP8 and rTTHC. In specific, we assessed the physical properties, the antigenicity, and the immunogenicity of conjugates for crosslinkers ranging in spacer-arm length from 1.5 to 95.2 Å, with varying hydrophobicity and crosslinking-functional groups. Conjugates coupled with different degrees of multimerization and peptide-to-rTTHC stoichiometry, but all were well recognized by HIV-fusion-peptide-directed antibodies VRC34.01, VRC34.05, PGT151, and ACS202 except for the conjugate with the longest linker (24-PEGylated SMCC; SM(PEG)24), which had lower affinity for ACS202, as did the conjugate with the shortest linker (succinimidyl iodoacetate; SIA), which also had the lowest peptide-to-rTTHC stoichiometry. Murine immunizations testing seven FP8-rTTHC conjugates elicited fusion-peptide-directed antibody responses, with SIA- and SM(PEG)24-linked conjugates eliciting lower responses than the other five conjugates. After boosting with prefusion-closed envelope trimers from strains BG505 clade A and consensus clade C, trimer-directed antibody-binding responses were lower for the SIA-linked conjugate; elicited neutralizing responses were similar, however, though statistically lower for the SM(PEG)24-linked conjugate, when tested against a strain especially sensitive to fusion-peptide-directed responses. Overall, correlation analyses revealed the immunogenicity of FP8-rTTHC conjugates to be negatively impacted by hydrophilicity and extremes of length or low peptide-carrier stoichiometry, but robust to other linker parameters, with several commonly used crosslinkers yielding statistically indistinguishable serological results.
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Johansson, Eva-Liz, Carola Rask, Margareta Fredriksson, Kristina Eriksson, Cecil Czerkinsky e Jan Holmgren. "Antibodies and Antibody-Secreting Cells in the Female Genital Tract after Vaginal or Intranasal Immunization with Cholera Toxin B Subunit or Conjugates". Infection and Immunity 66, n. 2 (1 febbraio 1998): 514–20. http://dx.doi.org/10.1128/iai.66.2.514-520.1998.
Testo completoAbstract (sommario):
ABSTRACT We studied the antibody response including antibody-secreting cells (ASC) in the female genital tract of mice after mucosal immunizations with the recombinant B subunit of cholera toxin (rCTB) perorally, intraperitoneally, vaginally, and intranasally (i.n.). The strongest genital antibody responses as measured with a novel perfusion-extraction method were induced after vaginal and i.n. immunizations, and these routes also gave rise to specific immunoglobulin A (IgA) and IgG ASC in the genital mucosa. Specific ASC in the iliac lymph nodes, which drain the female genital tract, were seen only after vaginal immunization. Progesterone treatment increased the ASC response in the genital tissue after all mucosal immunizations but most markedly after vaginal immunization. We also tested rCTB as a carrier for human gamma globulin (HGG) and the effect of adding cholera toxin (CT) as an adjuvant for the induction of systemic and genital antibody responses to HGG after vaginal and i.n. immunizations. Vaginal immunizations with HGG conjugated to rCTB resulted in high levels of genital anti-HGG antibodies whether or not CT was added, while after i.n. immunization the strongest antibody response was seen with the conjugate together with CT. In summary, vaginal and i.n. immunization give rise to a specific mucosal immune response including ASC in the genital tissue, and vaginal immunization also elicits ASC in the iliac lymph nodes. We have also shown that rCTB can act as an efficient carrier for a conjugated antigen for induction of a specific antibody response in the genital tract of mice after vaginal or i.n. immunization.
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Chen, Zhaochun, Rachel Schneerson, Julie A. Lovchik, Zhongdong Dai, Joanna Kubler-Kielb, Liane Agulto, Stephen H. Leppla e Robert H. Purcell. "Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax". Clinical and Vaccine Immunology 22, n. 8 (3 giugno 2015): 902–8. http://dx.doi.org/10.1128/cvi.00137-15.
Testo completoAbstract (sommario):
ABSTRACTThe immunogenicity ofBacillus anthraciscapsule (poly-γ-d-glutamic acid [PGA]) conjugated to recombinantB. anthracisprotective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >103were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 103. An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were ≤300, with the antibodies peaking above 104following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing ofB. anthracis. Most important, the PGA-TT–induced antibodies protected mice from a lethal challenge with virulentB. anthracisspores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines.
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Trad, Ahmad, Hinrich P. Hansen, Mohammad Shomali, Matthias Peipp, Katja Klausz, Nina Hedemann, Kosuke Yamamoto et al. "ADAM17-overexpressing breast cancer cells selectively targeted by antibody–toxin conjugates". Cancer Immunology, Immunotherapy 62, n. 3 (1 settembre 2012): 411–21. http://dx.doi.org/10.1007/s00262-012-1346-x.
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Bergquist, C., T. Lagergård, M. Lindblad e J. Holmgren. "Local and systemic antibody responses to dextran-cholera toxin B subunit conjugates." Infection and immunity 63, n. 5 (1995): 2021–25. http://dx.doi.org/10.1128/iai.63.5.2021-2025.1995.
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Sellrie, F., e B. Micheel. "Selection of recombinant antibody-producing E. coli cells by means of toxin conjugates". Biochemical Engineering Journal 38, n. 3 (marzo 2008): 309–13. http://dx.doi.org/10.1016/j.bej.2007.07.017.
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Tedder, T. F., V. S. Goldmacher, J. M. Lambert e S. F. Schlossman. "Epstein Barr virus binding induces internalization of the C3d receptor: a novel immunotoxin delivery system." Journal of Immunology 137, n. 4 (15 agosto 1986): 1387–91. http://dx.doi.org/10.4049/jimmunol.137.4.1387.
Testo completoAbstract (sommario):
Abstract Epstein Barr virus (EBV) infection of human B lymphocytes is initiated by selective binding of the virus to the C3d receptor (EBV/C3d receptor) on the cell surface and results in polyclonal proliferation of infected cells. In these studies we examined the fate of the EBV/C3d receptor during viral infection by using an immunotoxin made from a monoclonal antibody (HB5) reactive with the receptor and the potent toxin, gelonin. Binding of the HB5-gelonin conjugate to the EBV/C3d receptor before EBV infection (at concentrations as low as 10(-11) M) significantly inhibited the subsequent polyclonal proliferation of virus-infected B lymphocytes. HB5 antibody and gelonin alone did not inhibit proliferation. Because internalization of gelonin-antibody conjugates is required to cause cytotoxicity, these results indicate that infection of B lymphocytes with EBV selectively induced endocytosis of the EBV/C3d receptor with concomitant internalization of the immunotoxin. Proliferation of B lymphocytes that were activated by prior infection with EBV, or activated by cross-linking of their surface immunoglobulin molecules, was not inhibited by the antibody-toxin conjugate even at concentrations as high as 10(-7) M. Also, the growth of B lymphoblastoid cell lines cultured in the presence or absence of infectious EBV was not inhibited by HB5-gelonin. Thus, our results suggest that the EBV/C3d receptor is internalized only during the infection of normal B lymphocytes by EBV, with co-internalization of immunotoxin, and indicate that internalization of the EBV/C3d receptor-immunotoxin complex does not occur simply as a consequence of activation and proliferation of B lymphocytes. The use of a ligand to induce endocytosis of its receptor offers a new strategy for the selective delivery of immunotoxins to cells and may be more generally applicable.
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Price, Gregory A., Michael W. Russell e Cynthia Nau Cornelissen. "Intranasal Administration of Recombinant Neisseria gonorrhoeae Transferrin Binding Proteins A and B Conjugated to the Cholera Toxin B Subunit Induces Systemic and Vaginal Antibodies in Mice". Infection and Immunity 73, n. 7 (luglio 2005): 3945–53. http://dx.doi.org/10.1128/iai.73.7.3945-3953.2005.
Testo completoAbstract (sommario):
ABSTRACT The transferrin binding proteins (TbpA and TbpB) comprise the gonococcal transferrin receptor and are considered potential antigens for inclusion in a vaccine against Neisseria gonorrhoeae. Intranasal (IN) immunization has shown promise in development of immunity against sexually transmitted disease pathogens, in part due to the induction of antigen-specific genital tract immunoglobulin A (IgA) and IgG. Conjugation of antigens to the highly immunogenic cholera toxin B subunit (Ctb) enhances antibody responses in the serum and mucosal secretions following IN vaccination. In the current study, we characterized the anti-Tbp immune responses following immunization of mice IN with recombinant transferrin binding proteins (rTbpA and rTbpB) conjugated to rCtb. We found that both rTbpA-Ctb and rTbpB-Ctb conjugates administered IN induced antibody responses in the serum and genital tract. IN immunization resulted in both IgA and IgG in the genital tract; however, subcutaneous immunization mainly generated IgG. Surprisingly, rTbpA alone was immunogenic and induced serum and mucosal antibody responses similar to those elicited against the rTbpA-Ctb conjugate. Overall, rTbpB was much more immunogenic than rTbpA, generating serum IgG levels that were greater than those elicited against rTbpA. Bactericidal assays conducted with sera collected from mice immunized IN with TbpA and/or TbpB indicated that both antigens generated antibodies with bactericidal activity. Anti-TbpA antibodies were cross-bactericidal against heterologous gonococcal strains, whereas TbpB-specific antibodies were less cross-reactive. By contrast, antibodies elicited via subcutaneous immunization were not cross-bactericidal against heterologous strains, indicating that IN vaccination could be the preferred route for elicitation of biologically functional antibodies.
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Speirs, Joan I., e Mumtaz Akhtar. "Detection of Escherichia coli cytotoxins by enzyme-linked immunosorbent assays". Canadian Journal of Microbiology 37, n. 8 (1 agosto 1991): 650–53. http://dx.doi.org/10.1139/m91-110.
Testo completoAbstract (sommario):
Sandwich enzyme-linked immunosorbent assays (ELISAs) were developed to detect Escherichia coli cytotoxins. Wells were coated with monoclonal antibodies from hybridomas 13C4 and (or) 11E10, and biotin conjugates of these antibodies were used for detecting verotoxin 1 and Shiga-like toxin II, respectively. Sensitivities were about 100 and 200 cytotoxic doses, respectively. Verotoxin 2 was detected by ELISA with monoclonal antibody 11E10, but at a sensitivity of only about 4000 cytotoxic doses. ELISA results of polymyxin-treated cell extracts from cultures of 67 E. coli strains were in agreement with Vero cell assay as regards the presence and type of toxin. Key words: Escherichia coli, cytotoxin, ELISA.
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Seong, Seung-Yong, Nam-Hyuk Cho, Ick Chan Kwon e Seo Young Jeong. "Protective Immunity of Microsphere-Based Mucosal Vaccines against Lethal Intranasal Challenge withStreptococcus pneumoniae". Infection and Immunity 67, n. 7 (1 luglio 1999): 3587–92. http://dx.doi.org/10.1128/iai.67.7.3587-3592.1999.
Testo completoAbstract (sommario):
ABSTRACT Mucosal vaccination of capsular polysaccharide (PS) ofStreptococcus pneumoniae and subsequent creation of the first line of immunological defense in mucosa were examined. Mucosal as well as systemic antibody responses to PS were evoked by peroral or intranasal immunization of BALB/c mice with PS-cholera toxin B subunit (CTB) conjugates entrapped in the alginate microspheres (AM). The bacterial colonization at the lung mucosa was most profoundly inhibited (<95%) by intranasal immunization with the naked conjugate (PS-CTB). The mice vaccinated orally with encapsulated conjugate [AM(PS-CTB)] showed significant reduction on the level of pneumococcal bacteremia (<99%). Eighty percent of the mice perorally immunized with AM (PS-CTB) were protected from lethal intranasal challenge with S. pneumoniae, whereas more than 60% of the mice in the other control groups died of infection. Our novel approach may prove to be important in the development of a mucosal vaccine that will provide protection of mucosal surfaces of host.
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Polito, Letizia, Giulia Calafato, Massimo Bortolotti, Cecilia Chiarelli Olivari, Stefania Maiello e Andrea Bolognesi. "Antibody Conjugates for Sarcoma Therapy: How Far along Are We?" Biomedicines 9, n. 8 (8 agosto 2021): 978. http://dx.doi.org/10.3390/biomedicines9080978.
Testo completoAbstract (sommario):
Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy.
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Karsten, Lennard, Nils Janson, Vadim Le Joncour, Sarfaraz Alam, Benjamin Müller, Jayendrakishore Tanjore Ramanathan, Pirjo Laakkonen, Norbert Sewald e Kristian M. Müller. "Bivalent EGFR-Targeting DARPin-MMAE Conjugates". International Journal of Molecular Sciences 23, n. 5 (23 febbraio 2022): 2468. http://dx.doi.org/10.3390/ijms23052468.
Testo completoAbstract (sommario):
Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared the bivalent DARPin dimer (DD1) and a DARPin-Fc (DFc) to the monomeric DARPin (DM) and the antibody derived scFv425-Fc (scFvFc) in cell culture and a mouse model. The modular conjugation system, which was successfully applied for the preparation of protein-drug and -dye conjugates, uses bio-orthogonal protein-aldehyde generation by the formylglycine-generating enzyme (FGE). The generated carbonyl moiety is addressed by a bifunctional linker with a pyrazolone for a tandem Knoevenagel reaction and an azide for strain-promoted azide-alkyne cycloaddition (SPAAC). The latter reaction with a PEGylated linker containing a dibenzocyclooctyne (DBCO) for SPAAC and monomethyl auristatin E (MMAE) as the toxin provided the stable conjugates DD1-MMAE (drug-antibody ratio, DAR = 2.0) and DFc-MMAE (DAR = 4.0) with sub-nanomolar cytotoxicity against the human squamous carcinoma derived A431 cells. In vivo imaging of Alexa Fluor 647-dye conjugates in A431-xenografted mice bearing subcutaneous tumors as the SCC model revealed unspecific binding of bivalent DARPins to the ubiquitously expressed EGFR. Tumor-targeting was verified 6 h post-injection solely for DD1 and scFvFc. The total of four administrations of 6.5 mg/kg DD1-MMAE or DFc-MMAE twice weekly did not cause any sequela in mice. MMAE conjugates showed no significant anti-tumor efficacy in vivo, but a trend towards increased necrotic areas (p = 0.2213) was observed for the DD1-MMAE (n = 5).
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Peeters, C. C., A. M. Tenbergen-Meekes, C. J. Heijnen, J. T. Poolman, B. J. Zegers e G. T. Rijkers. "In vitro induction of a Haemophilus influenzae type b polysaccharide-specific antibody response in human peripheral blood lymphocytes of individuals recently vaccinated with an oligosaccharide-protein conjugate." Journal of Immunology 147, n. 12 (15 dicembre 1991): 4192–99. http://dx.doi.org/10.4049/jimmunol.147.12.4192.
Testo completoAbstract (sommario):
Abstract In this paper an in vitro culture system for the induction of an antibody response to the Haemophilus influenzae type b polysaccharide (PRP) is described. Anti-PRP IgM and IgG antibody-secreting cells (ASC) and anti-diphtheria toxoid (DT) IgG ASC were detected in cultures of blood B and T cells derived from donors 4 to 6 wk after immunization with Haemophilus influenzae type b oligosaccharide-mutant diphtheria toxin (CRM197) conjugate (HbOC) and required in vitro restimulation with HbOC. When lymphocytes from HbOC-vaccinated donors were stimulated with PRP, anti-PRP IgM and IgG ASC could be detected in 50% offGe cases. Lymphocytes from PRP-vaccinated donors or non-vaccinated donors consistently failed to generate anti-PRP antibodies after in vitro stimulation with HbOC. Optimal in vitro responses were observed at concentrations of 0.06 to 0.6 micrograms/ml of Ag. At higher doses of Ag (6 micrograms/ml) anti-PRP and anti-DT antibody responses were suppressed. The in vitro generation of anti-PRP and anti-DT ASC, as detected by a spot-forming cell assay was shown to be T cell dependent, Ag dependent, and Ag specific. This culture system provides a model for the study of human B cell activation and immunoregulation by polysaccharide-protein conjugates and polysaccharides.
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Lu, Ying-Jie, Sophie Forte, Claudette M. Thompson, Porter W. Anderson e Richard Malley. "Protection against Pneumococcal Colonization and Fatal Pneumonia by a Trivalent Conjugate of a Fusion Protein with the Cell Wall Polysaccharide". Infection and Immunity 77, n. 5 (2 marzo 2009): 2076–83. http://dx.doi.org/10.1128/iai.01554-08.
Testo completoAbstract (sommario):
ABSTRACT Cell wall polysaccharide (CWPS), pneumolysin, and surface adhesin A (PsaA) are antigens common to virtually all serotypes of Streptococcus pneumoniae (pneumococcus), and all have been studied separately for use in protection. Previously we showed that protection against nasopharyngeal (NP) colonization by intranasal vaccination of mice with killed pneumococci is mediated by TH17 cells and correlates with interleukin-17A (IL-17A) expression by T cells in vitro; we have also shown that CWPS and other species-common antigens protect against colonization by a similar mechanism. Here we made a fusion protein of PsaA with the pneumolysin nontoxic derivative PdT and then coupled CWPS to the fusion protein, aiming to enhance immune responses to all three antigens. When given intranasally with cholera toxin adjuvant, the fusion conjugate induced higher serum antibody titers and greater priming for IL-17A responses than an equimolar mixture of the three antigens. The conjugate administered intranasally protected mice against experimental NP colonization by a strain of serotype 6B, while mice immunized with the mixture or with bivalent conjugates were not protected. Subcutaneous immunization with the conjugate and alum adjuvant likewise induced higher antibody titers than the mixture, primed for IL-17A responses, and reduced colonization. The conjugate, but not the antigen mixture, fully protected mice from fatal pneumonia caused by a highly virulent serotype 3 strain. Thus, a covalent construct of three antigens common to all serotypes exhibits protection with both mucosal and systemic administration.
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Senter, Peter D., Marilyn J. Tansey, John M. Lambert e Walter A. Blattler. "NOVEL PHOTOCLEAVABLE PROTEIN CROSSLINKING REAGENTS AND THEIR USE IN THE PREPARATION OF ANTIBODY-TOXIN CONJUGATES". Photochemistry and Photobiology 42, n. 3 (settembre 1985): 231–37. http://dx.doi.org/10.1111/j.1751-1097.1985.tb08936.x.
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Liu, Yongheng, Wei Lian, Xi Zhao, Wei Qi, Jian Xu, Liang Xiao, Yan Qing, Tongtong Xue e Jingyi Wang. "A phase I study of safety and pharmacokinetics of A166, a novel selective inhibitor of human epidermal growth factor receptor-2 in Chinese patients with advanced solid tumors." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): e13007-e13007. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13007.
Testo completoAbstract (sommario):
e13007 Background: Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug (monomethyl auristatin F derivative ) site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker, which has a DAR (Drug Antibody Ratio) of Better efficacy were observed in preclinical CDX and PDX studies including HER2 low expression and T-DM1 resistant models while toxicity studies demonstrated a good safety profile in cynomolgus monkey. Methods: Patients with HER2-expressing or amplified advanced solid tumors refractory to standard therapies were recruited. A modified Fibonacci 3 + 3 dose-escalation design was employed with 7 dose levels (0.1, 0.3, 0.6, 1.2, 2.4, 3.6, and 4.8 mg/kg every 3 weeks). Safety analyses included all patients. PK and antitumor activity were also assessed. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose. Results: As of October 1, 2019 among 19 patients (breast cancer, colorectal cancer and gastric cancer)treated,no one experienced dose-limiting toxicity. No maximum tolerated dose was determined until 4.8mg/kg dose level. Grade≥3 adverse event was reported for 4 patient as neutropenia、anemia、Hyponatremia and Hypophosphatemia. Notably, 36.8% (n = 7) of patients experienced dry eye, as well as corneal epitheliopathy, and 2 patients withdraw from the study due to grade 2 corneal epitheliopathy. In 3.6 and 4.8 mg/kg groups, 6 patients were evaluable for tumor response, including 3 with partial response, 2 with stable disease. A166 exposure increased with the increase of dose, and extremely low exposure of free toxin and toxin-linker conjugates were observed; t1/2 was 8.29 days at the 4.8mg/kg. Conclusions: A166 showed an acceptable safety profile and promising anti-tumor activity in patients with HER2-expressing advanced solid tumors. Clinical trial information: CTR20181301 .
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Dardevet, Lucie, Feten Najlaoui, Sonia Aroui, Mayeul Collot, Céline Tisseyre, Michael W. Pennington, Jean-Maurice Mallet e Michel De Waard. "A Conjugate between Lqh-8/6, a Natural Peptide Analogue of Chlorotoxin, and Doxorubicin Efficiently Induces Glioma Cell Death". Biomedicines 10, n. 10 (17 ottobre 2022): 2605. http://dx.doi.org/10.3390/biomedicines10102605.
Testo completoAbstract (sommario):
Natural peptides isolated from animal venoms generally target cell surface receptors with high affinity and selectivity. On many occasions, some of these receptors are over-expressed in cancer cells. Herein, we identified Lqh-8/6 as a natural peptide analog of chlorotoxin, a proven and useful compound for the diagnosis and treatment of glioma. Lqh-8/6 and two other natural analogues were chemically synthesized for the first time and evaluated for their ability to label, detect and prevent glioma growth in vitro. We demonstrate that a biotinylated version of Lqh-8/6 allows both the labeling of glioma cell lines and the detection of glioma in brain sections of glioma allograft Fisher rats. Lqh-8/6 has intrinsic anti-invasive properties but is non-toxic to glioma cells. To confer anti-tumor properties to Lqh-8/6, we chemically coupled doxorubicin to the glioma-targeting peptide using click chemistry. To this end, we successfully chemically synthesized Lqh-8/6-azide and doxorubicin-alkyne without impairing the toxic nature of doxorubicin. The toxin–drug conjugate efficiently promotes the apoptosis of glioma cells in vitro. This example contributes to the concept that animal venom peptides constitute exquisite warheads for delivering toxic chemical conjugates, a parallel to the popular concept of antibody–drug conjugates for the treatment of cancer.
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Palanca-Wessels, Maria Corinna, e Oliver W. Press. "Advances in the treatment of hematologic malignancies using immunoconjugates". Blood 123, n. 15 (10 aprile 2014): 2293–301. http://dx.doi.org/10.1182/blood-2013-10-492223.
Testo completoAbstract (sommario):
Abstract Monoclonal antibody therapy has revolutionized cancer treatment by significantly improving patient survival both in solid tumors and hematologic malignancies. Recent technological advances have increased the effectiveness of immunotherapy leading to its broader application in diverse treatment settings. Immunoconjugates (ICs) consist of a cytotoxic effector covalently linked to a monoclonal antibody that enables the targeted delivery of its therapeutic payload to tumors based on cell-surface receptor recognition. ICs are classified into 3 groups based on their effector type: immunotoxins (protein toxin), radioimmunoconjugates (radionuclide), and antibody drug conjugates (small-molecule drug). Optimization of each individual component of an IC (antibody, linker, and effector) is essential for therapeutic efficacy. Clinical trials have been conducted to investigate the effectiveness of ICs in hematologic malignancies both as monotherapy and in multiagent regimens in relapsed/refractory disease as well as frontline settings. These studies have yielded encouraging results particularly in lymphoma. ICs comprise an exciting group of therapeutics that promise to play an increasingly important role in the management of hematologic malignancies.
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Hammond, Philip W., Omid Vafa, Jonathan Jacinto, Jost Vielmetter, Sher Karki, Sean Yoder, Greg Lazar et al. "A Humanized Anti-CD30 Monoclonal Antibody, XmAb™2513, with Enhanced In Vitro Potency Against CD30-Positive Lymphomas Mediated by High Affinity Fc-Receptor Binding." Blood 106, n. 11 (16 novembre 2005): 1470. http://dx.doi.org/10.1182/blood.v106.11.1470.1470.
Testo completoAbstract (sommario):
Abstract CD30 (also known as Ki-1), a member of the TNF-receptor superfamily, is normally expressed at low levels on activated lymphocytes and has been implicated in cell death and T-cell proliferation. CD30 is highly expressed in Hodgkin’s disease, (HD) and in Anaplastic Large Cell Lymphoma (ALCL). Unmodified CD30 antibodies as well as anti-CD30 based bi-specific antibodies, antibody-toxin conjugates, and radioimmuno-therapeutics have examined CD30 as a therapeutic target in preclinical and clinical studies. Unmodified antibodies have met with limited success and a lack of engagement of immune effector cells may be one of the major short-comings. Although bispecific antibodies proved among the most clinically effective through the recruiting of host effector functions to tumor cells, they pose significant manufacturing challenges. Similarly, toxin- and radio-conjugates require complicated manufacture and handling. Recent advances in antibody engineering have led to the development of “naked” antibodies with greatly enhanced effector function through mutagenesis at the Fc-receptor binding interface. This approach has been applied to a humanized antibody specific for CD30 to produce an antibody with enhanced potency and efficacy coupled with the ease of manufacture and handling of a traditional IgG antibody. The murine:human chimeric antibody cAC10 was humanized using the novel method of human string content optimization. The humanized antibody (hAC10) has an affinity for antigen 4-fold higher than that of the corresponding chimeric antibody. The humanized variable domain was then combined with a modified Fc region and exhibited an approximately 20 fold increase in affinity for the FcγRIIIA receptor resulting in the therapeutic lead XmAb2513. Expression levels from a stable cell-line were close to 1 gm/L in preliminary development. The cytotoxic activity of XmAb2513 was measured by Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assay. ADCC assays used PBMC’s isolated from peripheral blood as effector cells and the human Hodgkin’s cell line L540 which expresses high levels of CD30 as the target at an effector:target ratio of 25:1; cytotoxicity was measured by release of LDH or preloaded TDA. The activity of XmAb2513 was compared to that of cAC10 with no Fc-receptor binding enhancement (IgG1) as well as to the antibody 5F11 (also human IgG1). Significant improvements were observed in both potency (concentration of antibody required to effect 50% of maximal lysis) and efficacy (maximal percent lysis at saturating antibody concentration). The potency of XmAb2513 is ~3 fold higher than that of cAC10-IgG1 and 10-fold higher than 5F11 with an increase in efficacy of 4-fold relative to cAC10-IgG1. XmAb2513 has advantageous properties for a therapeutic compound against CD30-positive lymphomas including high levels of cytotoxicity and ease of manufacture and handling. The promising results reported herein clearly warrant further investigation.
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Porath, Kendra A., Ann Mladek, Rachael A. Vaubel, Michael S. Regan, Sonia Jain, Danielle Burgenske, Katrina Bakken et al. "Abstract 334: Convection enhanced delivery of EGFR-targeting antibody drug conjugates ABBV-321 and Depatux-M". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 334. http://dx.doi.org/10.1158/1538-7445.am2022-334.
Testo completoAbstract (sommario):
Abstract Introduction: EGFR targeted antibody-drug conjugates (ADCs) show promise as a novel treatment in a subset of glioblastoma (GBM). Two EGFR targeting ADCs include first generation Depatux-M, with an antimitotic toxin monomethyl auristatin F (MMAF), and ABBV-321, with a DNA crosslinking agent pyrrolobenzodiazepine dimer (PBD) toxin. Due to the large molecular weight, poor drug distribution across the blood-brain barrier significantly limits the efficacy in EGFR-amplified GBM. We studied whether convection enhanced delivery (CED) can be used to safely infuse these two EGFR-targeted ADCs in patient-derived xenograft (PDX) models of EGFR-amplified GBM. Methods: The efficacy of Depatux-M and ABBV-321 was evaluated in vitro and in vivo in two EGFRviii-amplified PDXs (GBM6 and GBM108). Immunofluorescence staining was used to evaluate drug distribution along with pharmacodynamics of the ADCs. CED was performed by stereotactic placement of an infusion catheter in the same location as the original tumor implantation. Immunohistochemistry was used to explore mechanisms of normal cell toxicity. Results: Despite potent activity in vitro (high ng/ml IC50), systemic administration of either ADC conferred minimal extension in survival for either GBM6 or GBM108. In contrast, CED significantly enhanced ADC delivery to tumor and peri-tumoral regions and extended survival. In a pilot study in GBM6 with n=3 mice per group, a single CED infusion of 0.002mg ABBV-321 resulted in extended survival beyond 365 days for two mice, while other doses and placebo were associated with shorter median survival (0 mg - 39 days; 0.03 mg - 105 days; 0.3 mg - 49 days). In a subsequent trial evaluating serial infusions performed every 21 days, four infusions at 0.002 mg ABBV-321 resulted in lethal toxicity. In contrast, limiting ABBV-321 to only two serial CED infusions in GBM108 was associated with extended survival of more than 300 days vs. 53 days for AB095 antibody control infusion. In contrast, serial infusion with Depatux-M was much better tolerated. In a single infusion in GBM6, a 0.06 mg dose was well tolerated and associated with a 49-day extension in median survival. Further, four serial infusions at 0.06 mg given every 21 days in GBM6 and GBM108 was associated with 100 day and more than 250-day extension in survival as compared to AB095 antibody control infusion. To investigate the mechanism of toxicity, infusion of non-tumor bearing C57Bl6 mice with ABBV-321 resulted in a marked loss in NeuN staining and elevated CD68 and GFAP staining 7 days later; Depatux-M infusion was only associated with modest elevation in GFAP without loss of NeuN staining or elevated CD68-positive cells. Conclusion: Depatux-M is well tolerated when infused into normal brain and results in extended survival in orthotopic GBM PDXs. In contrast, ABBV-321, with a distinct PBD toxin, had a much narrower therapeutic window when delivered by CED. Citation Format: Kendra A. Porath, Ann Mladek, Rachael A. Vaubel, Michael S. Regan, Sonia Jain, Danielle Burgenske, Katrina Bakken, Brett Carlson, Margaret Connors, Zeng Hu, Lihong He, Paul A. Decker, Gaspar Kitange, Shiv Gupta, Nathalie Y. Agar, Thomas M. Feldsien, Didier R. Lefebvre, Jann N. Sarkaria. Convection enhanced delivery of EGFR-targeting antibody drug conjugates ABBV-321 and Depatux-M [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 334.
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Ambrosino, D. M., D. Bolon, H. Collard, R. Van Etten, M. V. Kanchana e R. W. Finberg. "Effect of Haemophilus influenzae polysaccharide outer membrane protein complex conjugate vaccine on macrophages." Journal of Immunology 149, n. 12 (15 dicembre 1992): 3978–83. http://dx.doi.org/10.4049/jimmunol.149.12.3978.
Testo completoAbstract (sommario):
Abstract Haemophilus influenzae type b polysaccharide-conjugate vaccines elicit protective antibody responses in young infants. One of these conjugates, polysaccharide linked to outer membrane protein complex (PRP-OMPC), is produced by linking the capsular polysaccharide to an outer membrane protein complex derived from group B Neisseria meningitidis. The outer membrane protein complex contains T cell carrier epitopes that elicit T cell-dependent antibody responses. OMPC also has been shown to increase the antibody response to other proteins administered concurrently that are not covalently linked (i.e., acts as an adjuvant). In this study PRP-OMPC immunized mice demonstrated significant increases in spleen size as well as in splenocyte number as compared to saline controls (p < 0.01, p < 0.001, respectively). No such increase was noted after immunization with another H. influenzae type b-conjugate vaccine, oligosaccharide linked to a variant of diphtheria toxin. By analytic flow cytometry, the mice immunized with PRP-OMPC demonstrated an increase in large splenocytes expressing the Ag Mac-1 (CD11b, CR3). Furthermore, the spleens on histologic examination were characterized by an increase in the red pulp area consisting predominantly of cells of macrophage morphology. By immunohistochemical staining, the cells were identified as macrophages due to expression of Mac-1 and p150,95 (CD11C) Ag. After PRP-OMPC immunization, severe combined immunodeficient mice also demonstrated significant splenomegaly with an increase in macrophages identified by expression of Mac-1 and MHC class II Ag. Thus PRP-OMPC vaccine resulted in T cell-independent splenomegaly with an increase number of macrophages. We propose that this unique property may confer increased immunogenicity to PRP-OMPC through macrophage activation and cytokine release. Furthermore, the effect on macrophages may explain the "adjuvant" capacity of OMPC.
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Delprino, Laura, Maria Giacomotti, Franco Dosio, Paola Brusa, Maurizio Ceruti, Giorgio Grosa e Luigi Cattel. "Toxin-Targeted Design for Anticancer Therapy. II: Preparation and Biological Comparison of Different Chemically Linked Gelonin-Antibody Conjugates". Journal of Pharmaceutical Sciences 82, n. 7 (luglio 1993): 699–704. http://dx.doi.org/10.1002/jps.2600820706.
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Hamamichi, Shusei, Takeshi Fukuhara e Nobutaka Hattori. "Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities". Toxins 12, n. 10 (15 ottobre 2020): 658. http://dx.doi.org/10.3390/toxins12100658.
Testo completoAbstract (sommario):
Toxins, while harmful and potentially lethal, have been engineered to develop potent therapeutics including cytotoxins and immunotoxins (ITs), which are modalities with highly selective targeting capabilities. Currently, three cytotoxins and IT are FDA-approved for treatment of multiple forms of hematological cancer, and additional ITs are tested in the clinical trials or at the preclinical level. For next generation of ITs, as well as antibody-mediated drug delivery systems, specific targeting by monoclonal antibodies is critical to enhance efficacies and reduce side effects, and this methodological field remains open to discover potent therapeutic monoclonal antibodies. Here, we describe our application of engineered toxin termed a cell-based IT screening system. This unique screening strategy offers the following advantages: (1) identification of monoclonal antibodies that recognize cell-surface molecules, (2) selection of the antibodies that are internalized into the cells, (3) selection of the antibodies that induce cytotoxicity since they are linked with toxins, and (4) determination of state-specific activities of the antibodies by differential screening under multiple experimental conditions. Since the functional monoclonal antibodies with internalization capacities have been identified successfully, we have pursued their subsequent modifications beyond antibody drug conjugates, resulting in development of immunoliposomes. Collectively, this screening system by using engineered toxin is a versatile platform, which enables straight-forward and rapid selection for discovery of novel functional antibodies.
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Riedl, Thilo, Egon van Boxtel, Martijn Bosch, Paul W. H. I. Parren e Arnout F. Gerritsen. "High-Throughput Screening for Internalizing Antibodies by Homogeneous Fluorescence Imaging of a pH-Activated Probe". Journal of Biomolecular Screening 21, n. 1 (30 ottobre 2015): 12–23. http://dx.doi.org/10.1177/1087057115613270.
Testo completoAbstract (sommario):
Antibody-drug conjugates (ADCs) represent a rapidly growing class of biotherapeutics that deliver drugs specifically to target cells by binding of the antibody component to surface receptors. The majority of ADCs require receptor internalization depending on intrinsic features of the specific ADC-antigen interaction. The development of potent ADCs would greatly benefit from the identification of efficiently internalizing antibodies at early stages of discovery. We developed a highly sensitive and rapid antibody internalization assay using an indirect Cypher5E label. The pH-activated CypHer5E label becomes fluorescent upon internalization into the acidic environment of endocytic organelles, whereas background fluorescence of noninternalized CypHer5E is minimal. The pH-dependency of the CypHer5E signal enables robust discrimination of antibody internalization from surface binding. The favorable signal-over-background ratio allows a homogeneous assay design with high-throughput fluorescence imaging in 384- and 1536-well formats. The biophysical readout of the primary internalization event substantially shortens incubation times compared to killing assays using toxin internalization. The assay was validated with tumor-relevant targets, including receptor tyrosine kinases (EGFR and HER2) and a class II cytokine receptor (TF) expressed by A431, AU565, and SKOV-3 cells and transient expression systems (CHO-S). Our method enables functional screening of large antibody libraries to identify therapeutic antibody candidates with internalization characteristics favorable for the development of ADCs.
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Passwell, Justen H., Efrat Harlev, Shai Ashkenazi, Chiayung Chu, Dan Miron, Reut Ramon, Naheed Farzan et al. "Safety and Immunogenicity of ImprovedShigella O-Specific Polysaccharide-Protein Conjugate Vaccines in Adults in Israel". Infection and Immunity 69, n. 3 (1 marzo 2001): 1351–57. http://dx.doi.org/10.1128/iai.69.3.1351-1357.2001.
Testo completoAbstract (sommario):
ABSTRACT Data suggest that the O-specific polysaccharide (O-SP) domain of the lipopolysaccharide (LPS) of Shigella species is both an essential virulence factor and a protective antigen and that a critical level of serum immunoglobulin G (IgG) to this antigen will confer immunity to shigellosis. Because covalent attachment of polysaccharides to proteins increases their immunogenicity, especially in infants and in young children, the O-SP of Shigella species were bound to medically useful proteins, and the safety and immunogenicity of the resultant conjugates were confirmed in adults and 4- to 7-year-old children. Succinylation of the carrier protein improved the immunogenicity of Shigella conjugates in mice and increased their yield. Based on these results, a clinical trial of O-SP conjugates of Shigella sonnei and Shigella flexneri 2a bound to succinylated mutant Pseudomonas aeruginosa exotoxin A (rEPAsucc) or native or succinylated Corynebacterium diphtheriae toxin mutant (CRM9 or CRM9succ) was conducted in healthy adults. The conjugates were safe and immunogenic. S. sonnei-CRM9,S. sonnei-CRM9succ, and S. sonnei-rEPAsucc elicited significant rises of geometric mean (GM) IgG anti-LPS within 1 week of injection (P < 0.001). At 26 weeks, the GM anti-LPS levels elicited by these three conjugates were similar and higher than their prevaccination levels (P < 0.0001). GM IgG anti-LPS levels elicited by S. flexneri2a-rEPAsucc were significantly higher than those elicited by S. flexneri 2a-rCRM9succ at all intervals after injection. At 26 weeks, the levels of IgG anti-LPS in vaccinees were higher than their prevaccination levels (P < 0.0001). The serum antibody responses were specific, as there was no significant rise of anti-LPS to the heterologous O-SP in any vaccinee. Both conjugates elicited statistically significant rises of serum antibodies to the injected carrier protein. At 6 months, these five Shigellaconjugates elicited higher fold rises than similar conjugates (D. N. Taylor et al., Infect. Immun. 61:3678–3687, 1993). Based on these data, we chose S. sonnei-CRM9 and S. flexneri2a-rEPAsucc for evaluation in children.
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Pestka, James J. "Enhanced Surveillance of Foodborne Mycotoxins by Immunochemical Assay". Journal of AOAC INTERNATIONAL 71, n. 6 (1 novembre 1988): 1075–81. http://dx.doi.org/10.1093/jaoac/71.6.1075.
Testo completoAbstract (sommario):
Abstract Mycotoxins are a chemically diverse group of fungal secondary metabolites with a wide range of toxic effects. Conventional thin-layer and instrumental methods of mycotoxin analysis are time-consuming and make routine safety and quality control screening of these compounds in agricultural commodities difficult. As an alternative, specific polyclonal and monoclonal antibodies have been raised against mycotoxin-protein conjugates and used in sensitive radioimmunoassays (RIAs) and enzyme-linked immunosorbent assays (ELISAs). One of the simplest ELISA approaches involves competition for a solid-phase antibody between a mycotoxin-enzyme conjugate and an unconjugated mycotoxin in the sample extract. ELISAs have been developed for aflatoxins B, and M„ zearalenone, T-2 toxin, and deoxynivalenol, which are highly specific, rapid (10 min), easily adaptable for analyzing large numbers of samples, and directly applicable to assaying methanol-water extracts of a wide range of foods. Several commercial mycotoxin ELISAs using this approach (most typically for aflatoxin B,) are currently being marketed. Since ELISAs will be used in large part by personnel with limited technical expertise, individual kits must be critically evaluated by analytical chemists for suggested sampling procedures, efficiency of extraction, crossreactivity, mycotoxin recovery, assay reproducibility, and product shelf-life prior to routine use in food safety and quality control screening
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Niculescu-Duvaz, I., e C. J. Springer. "Antibody-Directed Enzyme Prodrug Therapy (ADEPT): A Targeting Strategy in Cancer Chemotherapy". Current Medicinal Chemistry 2, n. 3 (ottobre 1995): 687–706. http://dx.doi.org/10.2174/092986730203220223143057.
Testo completoAbstract (sommario):
<P>Antibody-Directed Enzyme Prodrug Therapy (ADEPT) is a new conceptual approach designed to improve the selectivity of anti-cancer drugs. ADEPT separates the cytotoxic from the targeting function of immunoconjugates in a two phase system that has benefits over one phase chemo-, toxin- or radio-immunoconjugates. <P> This review, while discussing the basic prinicples of ADEPT and the main requirements for all the components (enzymes, prodrugs and antibodies) of the systems, also summarizes the latest results obtained with this technolo gy. The main components of ADEPT are described. These include the targeting of cancer cells by the antibody-enzyme conjugates, the enzymatic activation of the prodrugs, the selection of the prodrug/drug (and/or enzyme/prodrug) systems. A special emphasis has been placed on the prodrug/drug systems, the rationale behind their design and the in vitro and in vivo results obtained with the different types of the prodrugs. <P> The analysis of the advantages and disadvantages of the ADEPT system has led to the potential for clinical use of this sytem, which enables higher drug concentrations at the tumor compared to classical chemotherapy.</P>
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Laske, Douglas W., Orhan Ilercil, Aytac Akbasak, Richard J. Youle e Edward H. Oldfield. "Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice". Journal of Neurosurgery 80, n. 3 (marzo 1994): 520–26. http://dx.doi.org/10.3171/jns.1994.80.3.0520.
Testo completoAbstract (sommario):
✓ Targeted protein toxins are a new class of reagents with the potential for great tumor selectivity and cytotoxic potency. Two such compounds were studied: 1) Tf-CRM107, a conjugate of human transferrin (Tf) and diphtheria toxin with a point mutation (CRM107); and 2) 454A12-rRA, a conjugate of a monoclonal antibody (454A12) to the human Tf receptor and recombinant ricin A chain (rRA). Both compounds are potent and specific in killing human glioblastoma cell lines in vitro. The authors investigated the activity of these reagents administered intratumorally against solid U251 MG human gliomas in vivo. Nude mice with established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were randomly assigned to be treated with 100-µl intratumoral injections of Tf-CRM107 (10 µg) or 454A12-rRA (10 µg), equimolar doses of CRM107 (4.3 µg), 454A12 antibody (7.5 µg), or rRA (1.5 µg), or phosphate-buffered saline (PBS) every 2 days for a total of four doses. Tumor volume and animal weight were assessed by a blinded observer before each treatment and biweekly for 30 days after initiating therapy. With Tf-CRM107 administration, tumor regression of greater than 95% occurred by Day 14 (p < 0.01) and tumors did not recur by Day 30. Treatment with 454A12-rRA caused a 30% decrease in tumor volume by Day 14 (p < 0.01). Treatment with equimolar doses of the unconjugated targeted protein toxin components CRM107, 454A12, or rRA caused significant U251 MG tumor growth inhibition, but the effects were less potent than the antitumor effects of the conjugates. This study also characterized the dose-response effect of Tf-CRM107 on tumor growth and tumor weight on Day 30. Nude mice with established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were treated with 100-µl intratumoral injections of 10, 1.0, or 0.1 µg of Tf-CRM107 or PBS every 2 days for a total of four doses. All three doses of Tf-CRM107 significantly inhibited tumor growth by Day 14 (p < 0.01) and at Day 30 (p < 0.05), with a significant dose-response relationship. This study demonstrated in vivo efficacy of the targeted toxins Tf-CRM107 and 454A12-rRA against a human glioma. With intratumoral administration, the effect of Tf-CRM107 was tumor-specific and in some animals curative. Regional therapy with these potent tumor-specific agents using direct intratumoral infusion should limit systemic toxicity and may be efficacious against brain tumors.
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Shi, Xiarong, Leiliane P. Sousa, Elizabeth M. Mandel-Bausch, Francisco Tome, Andrey V. Reshetnyak, Yaron Hadari, Joseph Schlessinger e Irit Lax. "Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition". Proceedings of the National Academy of Sciences 113, n. 33 (1 agosto 2016): E4784—E4793. http://dx.doi.org/10.1073/pnas.1610179113.
Testo completoAbstract (sommario):
Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants.
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Maniecki, Maciej Bogdan, Henrik Hasle, Knud Bendix e Holger Jon Møller. "Hepatotoxicity in Patients Treated with Gemtuzumab Ozogamicin - Specific Targeting of Hepatocytes?" Blood 114, n. 22 (20 novembre 2009): 4150. http://dx.doi.org/10.1182/blood.v114.22.4150.4150.
Testo completoAbstract (sommario):
Abstract Abstract 4150 The immunotoxin gemtuzumab ozogamicin (Mylotarg‘, GO) comprises a potent cytotoxic agent, calicheamicin, and a recombinant humanized monoclonal antibody directed against CD33. GO is increasingly used for treatment of acute myeloid leukemia (AML) as CD33, a trans-membranous glycoprotein, is highly expressed on most leukemic blast cells, but, in normal cells confined to early multilineage hematopoietic progenitors and myelomonocytic precursors. Adverse effects of GO treatment are primarily related to myelosuppression (infections, fever, bleedings). However, severe sinusoidal obstructive syndrome (SOS) and hepatotoxicity have also been reported. Since the introduction of GO treatment into routine clinical practice, the incidence of SOS has been reported to span from 0% to 33%, but, the direct cause of the liver-associated effects remain unknown. Using immunohistochemistry we show that the CD33 receptor is widely distributed in the liver tissue and highly expressed on hepatocytes making them susceptible for targeted CD33 chemotherapy by GO. Moreover, utilizing CD163 as a specific marker for macrophages, double immunofluorescence staining revealed that Kupffer cells strongly express CD33. Therefore, the reported hepatoxicity associated with GO treatment may be due to accumulation of antibody-toxin conjugates in hepatocytes and Kupffer cells causing calicheamicin-induced damage. Disclosures: No relevant conflicts of interest to declare.
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Valent, Peter, Irina Sadovnik, Gregor Eisenwort, Karin Bauer, Harald Herrmann, Karoline V. Gleixner, Axel Schulenburg, Werner Rabitsch, Wolfgang R. Sperr e Dominik Wolf. "Immunotherapy-Based Targeting and Elimination of Leukemic Stem Cells in AML and CML". International Journal of Molecular Sciences 20, n. 17 (29 agosto 2019): 4233. http://dx.doi.org/10.3390/ijms20174233.
Testo completoAbstract (sommario):
The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must have the potential to eliminate or completely suppress LSC, as only these cells can restore and propagate the malignancy for unlimited time periods. Since LSC represent a minor cell fraction in the leukemic clone, little is known about their properties and target expression profiles. Over the past few years, several cell-specific immunotherapy concepts have been developed, including new generations of cell-targeting antibodies, antibody–toxin conjugates, bispecific antibodies, and CAR-T cell-based strategies. Whereas such concepts have been translated and may improve outcomes of therapy in certain lymphoid neoplasms and a few other malignancies, only little is known about immunological targets that are clinically relevant and can be employed to establish such therapies in myeloid neoplasms. In the current article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field.
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Bendell, Johanna C., Judy Sing-Zan Wang, Babar Bashir, Debra L. Richardson, Gavin Bennett, Carly Campbell, Meliessa G. Hennessy et al. "BT5528-100 phase I/II study of the safety, pharmacokinetics, and preliminary clinical activity of BT5528 in patients with advanced malignancies associated with EphA2 expression." Journal of Clinical Oncology 38, n. 15_suppl (20 maggio 2020): TPS3655. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3655.
Testo completoAbstract (sommario):
TPS3655 Background: BT5528 is a Bicycle Toxin Conjugate (BTC), comprising a bicyclic peptide targeting the tumor antigen EphA2, linked to a cytotoxin (monomethyl auristatin E [MMAE]) via a tumor microenvironment cleavable linker. Bicycles are a novel class of chemically synthesized constrained peptides, developed by Bicycle Therapeutics. EphA2 is reported to be overexpressed in a range of solid tumors, contributes to oncogenesis, tumor-associated angiogenesis and metastasis. Intracellular EphA2 signaling converges on pathways that are integral to cell growth, proliferation, migration and invasion. Increased EphA2 expression has been identified as a resistance mechanism to EGFR Tyrosine Kinase Inhibitor based therapy. BT5528 mechanism of action is dependent on tumor penetration, target binding and release of MMAE toxin payload. BTCs offer advantages over antibody-toxin conjugates exhibiting rapid penetration of dense tumors and decreased extra-tumor exposure. BT5528 exhibited a favorable preclinical profile supporting the initiation of a first-in-human study to investigate safety and efficacy of BT5528 in indications with evidence of EphA2 expression including non-small-cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI), pancreatic and urothelial cancers. Methods: BT5528-100 (NCT04180371) is a Ph I/II study to evaluate safety and tolerability of weekly BT5528 alone and in combination with Q4W nivolumab. Each dose escalation utilizes a 3+3 design which converts to a Bayesian design to determine MTD or MAD and RP2D for BT5528 with and without nivolumab. Eligible patients must have advanced solid tumors associated with EphA2 expression which have recurred after exhausting standard treatment options. Patients must have available tumor tissue and acceptable hematologic and organ function, with exclusions for uncontrolled brain metastases, thromboembolic events, bleeding disorders, uncontrolled hypertension, CYP3A4 inhibitors/inducers or, for the nivolumab cohorts, autoimmune disease. On-study tumor and blood samples will be collected for biomarker evaluations including tumor EphA2 expression, ADA, and candidate response biomarkers for BT5528 alone and combination with nivolumab. Pharmacokinetic data will be reported for C1D1 and D15 for BT5528 and MMAE. The expansion phase will enroll specific tumor types to evaluate clinical activity of BT5528. Enrollment is ongoing. Clinical trial information: NCT04180371 .
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Cabello-Alemán, Lucía. "Future directions in cancer immunotherapy with monoclonal antibodies". Research Results in Pharmacology 8, n. 4 (15 dicembre 2022): 101–7. http://dx.doi.org/10.3897/rrpharmacology.8.85918.
Testo completoAbstract (sommario):
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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Mahheidari, Naimeh, Jamal Rashidiani, Hamid Kooshki e Khadijeh Eskandari. "An Effort to Making a Colorimitric Nano-Biosensor for Vibrio cholera Detection". Current Nanoscience 16, n. 5 (5 ottobre 2020): 793–804. http://dx.doi.org/10.2174/1573413716666191230154316.
Testo completoAbstract (sommario):
Background: Today, nanoparticles hold great promise in biomedical researches and applications including bacteria detection. The rapid and sensitive outcomes of bacteria detection strategies using nanoparticle conjugates become determinative, especially in bacterial outbreaks. In the current research, we focused on detecting V. cholera bacteria and its toxin using a thiocyanate/Au nanoparticle. Thiocyanate adsorbed strongly on the surface of gold nanoparticles and changed the surface by enhancing surface plasmon resonance of gold nanoparticles. Objective: This method is tried to introduce a simple and fast procedure to assay vibrio cholera. So, it is observed by the naked eyes as well. Methods: We used two antibodies (Ab) for V. cholera detection: a) a primary antibody conjugated to magnetic nanoparticles (MNPs) for trapping V. cholera bacterial cells, and b) a secondary Abconjugated thiocyanate-GNPs as a colorimetric detector. Then, an immuno-magnetic separation system connected to a colorimetric assay was designed based on the GNPs. The results were measured by ultraviolet-visible (UV-Vis) spectroscopy. Results: The results showed that gold nanoparticles are an appropriate optical assay for detecting biological samples in a minimum concentration and also it can be easily seen by the naked eyes. The linear range of this biosensor is 3.2×104 to 28×104 cells per ml. Conclusion: In this research, a colorimetric immune assay based on gold nanoparticles was designed to improve the sensitivity of V. cholera detection. Also, this method can be used for the detection of other biological agents.
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Akter, Sultana, Teemu Kustila, Janne Leivo, Gangatharan Muralitharan, Markus Vehniäinen e Urpo Lamminmäki. "Noncompetitive Chromogenic Lateral-Flow Immunoassay for Simultaneous Detection of Microcystins and Nodularin". Biosensors 9, n. 2 (18 giugno 2019): 79. http://dx.doi.org/10.3390/bios9020079.
Testo completoAbstract (sommario):
Cyanobacterial blooms cause local and global health issues by contaminating surface waters. Microcystins and nodularins are cyclic cyanobacterial peptide toxins comprising numerous natural variants. Most of them are potent hepatotoxins, tumor promoters, and at least microcystin-LR is possibly carcinogenic. In drinking water, the World Health Organization (WHO) recommended the provisional guideline value of 1 µg/L for microcystin-LR. For water used for recreational activity, the guidance values for microcystin concentration varies mostly between 4–25 µg/L in different countries. Current immunoassays or lateral flow strips for microcystin/nodularin are based on indirect competitive method, which are generally more prone to sample interference and sometimes hard to interpret compared to two-site immunoassays. Simple, sensitive, and easy to interpret user-friendly methods for first line screening of microcystin/nodularin near water sources are needed for assessment of water quality and safety. We describe the development of a two-site sandwich format lateral-flow assay for the rapid detection of microcystins and nodularin-R. A unique antibody fragment capable of broadly recognizing immunocomplexes consisting of a capture antibody bound to microcystins/nodularin-R was used to develop the simple lateral flow immunoassay. The assay can visually detect the major hepatotoxins (microcystin-LR, -dmLR, -RR, -dmRR, -YR, -LY, -LF -LW, and nodularin-R) at and below the concentration of 4 µg/L. The signal is directly proportional to the concentration of the respective toxin, and the use of alkaline phosphatase activity offers a cost efficient alternative by eliminating the need of toxin conjugates or other labeling system. The easy to interpret assay has the potential to serve as a microcystins/nodularin screening tool for those involved in water quality monitoring such as municipal authorities, researchers, as well as general public concerned of bathing water quality.
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Wrobel, Charles J., Donald C. Wright, Robert L. Dedrick e Richard J. Youle. "Diphtheria toxin effects on brain-tumor xenografts". Journal of Neurosurgery 72, n. 6 (giugno 1990): 946–50. http://dx.doi.org/10.3171/jns.1990.72.6.0946.
Testo completoAbstract (sommario):
✓ A model was developed to determine whether protein-based chemotherapeutic agents can cross the blood-brain barrier and successfully treat brain tumors. The human small-cell lung carcinoma N417D was grown as a solid tumor in the nude rat brain, and diphtheria toxin (DT) was administered intravenously as therapy. Because rat cells lack functional DT receptors and are 1000 to 10,000 times less sensitive to DT than human cells, a therapeutic window exists between the implanted human tumor and the nude rat host. The pharmacokinetic and pharmacodynamic characteristics of DT were defined. Within 6 hours, more than 90% of the initial DT concentration was removed from the blood. The blood-to-tumor transfer constant Ki for DT in small N417D tumors was 0.49 µl/gm-min, one-fourth to one-fifth the reported values for permeability to proteins in other experimental tumor models. Despite the toxin's short plasma half-life and the relatively intact blood-tumor barrier, DT administered intravenously as a single dose significantly extended animal survival. Untreated nude rats developed solid parenchymal tumors and died in 11 to 16 days (median 15 days). When administered at 0.1 µg/animal, DT increased the median survival time to 19 days (p < 0.0016) while 1.0-µg doses extended median survival times to 26.5 days (p < 0.0002). A higher dose of DT (3.0 µg) had no further beneficial effect on survival (26.1 days). Blood-brain barrier constraints to successful monoclonal antibody-based therapies of brain tumors may have been overestimated since antibody conjugates have plasma half-lives longer than DT, and the permeability of N417D tumors to DT is equal to or less than the permeability of other experimental tumors to large proteins. Recently developed immunotoxins that have the higher potency of DT and a therapeutic window as wide as DT has in this nude rat/human tumor paradigm may be effective in treating brain tumors despite limited blood-tumor permeability.
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Budde, Lihua Elizabeth, Armen Mardiros, Wen-Chung Chang, Xiuli Wang, Carolina Berger, Christine Brown, Stanley R. Riddell, Oliver W. Press e Stephen J. Forman. "Truncated Cell-Surface CD19 As a Conditional Suicide Switch For Adoptive T Cell Immunotherapy". Blood 122, n. 21 (15 novembre 2013): 1660. http://dx.doi.org/10.1182/blood.v122.21.1660.1660.
Testo completoAbstract (sommario):
Background Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe Methods for removing transferred cells after treatment an important consideration. In addition, there is a lack of effective commercially available agents which allow for monitoring of CAR expression, tracking, isolating, and eliminating CAR- transduced cells. Therefore, adoptive T cell immunotherapy would benefit from a molecule which is stably expressed on the cell surface, of human origin, easily detected on transduced cells, lacking active biological function at baseline and capable of effectively ablating transduced cells on demand. Truncated CD19 (CD19t) harbors excellent features to be such a molecule. Its truncation shortens the intracytoplasmic domain to only 19 amino acids with removal of all conserved tyrosine residues that mediate known intracellular signaling transduction. It has been used successfully to mark transduced CAR T cells by several research groups. In this study, we set out to evaluate the activity of this truncated CD19 as a conditional suicide switch. Methods Lentiviral constructs containing a CD20 CAR and CD19t were used to transduce Jurkat T cells and primary human T cells to generate cells that express both molecules on the cell surface. CD19-mediated selection was carried out using PE conjugated anti-CD19 antibody. Internalization experiments were performed using transduced Jurkat cells that were kept at 4°C or 37°C. Surface CD19 expression was determined by flow cytometric analysis at 0 hour, 1 hour, 2 hours, and 4 hours after initial primary anti-CD19 antibody staining. NIH3T3 cells with truncated CD19 expressed on the surface (NIH3T3-19t) were generated and used for in vitro ablation experiments. Cells were left untreated or incubated withincreasing concentrations of CD19-ETA’, an anti-CD19 Pseudomonas toxin conjugate. The viability of NIH3T3-CD19t was determined by trypan blue exclusion at various time points. Results Using flow cytometry, we confirmed the expression of CAR and truncated CD19 on the transduced cell surface. Truncated CD19 was able to enrich transduced cells to more than 90% purity when used as a selectable marker. For CD19t to function as a conditional suicide switch, it needs to retain its ability to mediate antigen-antibody conjugate internalization. As expected, only up to 10% of CD19t remained on the surface of transduced cells after 4-hour period at 37°C. On the contrary, surface CD19t expression level remained largely unchanged when the cells were incubated at 4°C for 4 hours. CD19t also mediated robust ablation of transduced cells in vitro. More than 90% of transduced cells were ablated after 72-hour incubation with 10ug/ml CD19-ETA’. Mouse xenograft experiments are currently ongoing to test the in vivo tracking ability of CD19t and its ablation effect of transferred T cells upon administration of anti-CD19-drug conjugates. Conclusions These in vitro Results suggest that CD19t retains the ability to mediate antibody internalization upon its engagement. When exposed to an anti-CD19-drug conjugate, cells expressing truncated CD19 are effectively ablated in a dose dependent manner. We therefore predict that CD19t will be an excellent molecule to mark, select, track and eliminate modified T cells in vivo and it will be a useful tool for detection of engineered T cells and improvement of the safety of adoptive T cell immunotherapy. Disclosures: No relevant conflicts of interest to declare.
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Eriksson, Kristina, Margareta Fredriksson, Inger Nordström e Jan Holmgren. "Cholera Toxin and Its B Subunit Promote Dendritic Cell Vaccination with Different Influences on Th1 and Th2 Development". Infection and Immunity 71, n. 4 (aprile 2003): 1740–47. http://dx.doi.org/10.1128/iai.71.4.1740-1747.2003.
Testo completoAbstract (sommario):
ABSTRACT Cholera toxin (CT) is a strong mucosal adjuvant for codelivered antigens, whereas its nontoxic B subunit (CTB) is an efficient mucosal carrier molecule for the generation of immune responses to linked antigens. We investigated the effects of CT and CTB on the immunogenicity of in vitro-treated antigen-pulsed dendritic cells (DC) following intravenous injection into mice. Prior to infusion, DC were pulsed for 90 min with either free ovalbumin (OVA), OVA mixed with CT or CTB, or chemical conjugates of OVA with CT and CTB (OVA-CT and OVA-CTB). DC pulsed with OVA or with OVA and CTB gave rise to modest antibody and T-cell responses. Conjugation of OVA with CTB enhanced both the subsequent B-cell and T-cell responses to OVA and preferentially induced Th2 responses. CT was shown to be a strong adjuvant when it was coadministered to DC with OVA and was even stronger when it was coadministered with OVA-CTB and primed for a mixed Th1-Th2 response. The antibody and T-cell responses were further enhanced if OVA was coupled to CT, implying that CT can utilize a combined carrier and adjuvant function vis-a-vis linked antigens for DC vaccination. The immunopotentiating capacity of CT- and CTB-linked antigen was associated with both upregulated secretion of interleukin-1β by the pulsed DC and increased expression of CD80 and CD86 on the DC surface. These results imply that CT and CTB can be used to both markedly increase and partially direct the DC vaccine-induced immune response with respect to Th1 and Th2 responses, which has obvious implications for DC-based vaccine development.