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Journal articles on the topic 'Bispecific; BsAb; T cells'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Link, BK, and GJ Weiner. "Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells." Blood 81, no. 12 (1993): 3343–49. http://dx.doi.org/10.1182/blood.v81.12.3343.bloodjournal81123343.

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Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cel

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Link, BK, and GJ Weiner. "Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells." Blood 81, no. 12 (1993): 3343–49. http://dx.doi.org/10.1182/blood.v81.12.3343.3343.

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Abstract Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybr

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3

Velasquez, Mireya Paulina, Challice L. Bonifant, and Stephen Gottschalk. "Redirecting T cells to hematological malignancies with bispecific antibodies." Blood 131, no. 1 (2018): 30–38. http://dx.doi.org/10.1182/blood-2017-06-741058.

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Abstract There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an “off-the-shelf” product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb

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He, Xiao, Yanliang Zhang, Yun Wei Lai, et al. "Preclinical Characterization of an ANTI-CD38/CD3 T CELL-Redirecting Bispecific Antibody." Blood 134, Supplement_1 (2019): 4463. http://dx.doi.org/10.1182/blood-2019-131540.

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Introduction: Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL) are hematologic malignancies that remain difficult to treat. While autologous CAR-T cell therapies have shown promise in treating these diseases, these therapies are not without issues, including lack of response in many patients, lengthy time to produce CAR-T cells, occasional production failures, as well as high manufacturing costs. As an alternative approach, protein-based T cell engaging and redirecting bispecific antibodies (BsAbs) have been developed. We have generated anti-CD38/CD3 BsAbs to redirect T cells against CD38,

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DiLillo, David J., Kara Olson, Katja Mohrs, et al. "A BCMAxCD3 bispecific T cell–engaging antibody demonstrates robust antitumor efficacy similar to that of anti-BCMA CAR T cells." Blood Advances 5, no. 5 (2021): 1291–304. http://dx.doi.org/10.1182/bloodadvances.2020002736.

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Abstract CD3-engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells are potent therapeutic approaches for redirecting patient T cells to recognize and kill tumors. Here we describe a fully human bsAb (REGN5458) that binds to B-cell maturation antigen (BCMA) and CD3, and compare its antitumor activities vs those of anti-BCMA CAR T cells to identify differences in efficacy and mechanism of action. In vitro, BCMAxCD3 bsAb efficiently induced polyclonal T-cell killing of primary human plasma cells and multiple myeloma (MM) cell lines expressing a range of BCMA cell surf

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Sun, Rui, Yuexian Zhou, Lei Han, et al. "A Rational Designed Novel Bispecific Antibody for the Treatment of GBM." Biomedicines 9, no. 6 (2021): 640. http://dx.doi.org/10.3390/biomedicines9060640.

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Epidermal growth factor receptor variant III (EGFRvIII) is highly and specifically expressed in a subset of lethal glioblastoma (GBM), making the receptor a unique therapeutic target for GBM. Recently, bispecific antibodies (BsAbs) have shown exciting clinical benefits in cancer immunotherapy. Here, we report remarkable results for GBM treatment with a BsAb constructed by the “BAPTS” method. The BsAb was characterized through LC/MS, SEC-HPLC, and SPR. Furthermore, the BsAb was evaluated in vitro for bioactivities through FACS, antigen-dependent T-cell-mediated cytotoxicity, and a cytokine secr

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Demanet, C., J. Brissinck, J. De Jonge, and K. Thielemans. "Bispecific antibody-mediated immunotherapy of the BCL1 lymphoma: increased efficacy with multiple injections and CD28-induced costimulation." Blood 87, no. 10 (1996): 4390–98. http://dx.doi.org/10.1182/blood.v87.10.4390.bloodjournal87104390.

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The BCL1 lymphoma in Balb/c mice can be successfully treated with bispecific (anti-CD3 x anti-idiotype) antibodies (BSABs). In these experiments, animals were injected intraperitoneally (IP) with 5 x 10(3) tumor cells (day 0) and treated with one single intravenous (IV) injection of 5 micrograms BSAB (day 9). Because cross-linking of the CD3 complex is not in itself sufficient to activate resting T cells, the therapeutic success was mainly based on the progressive retargeting of the relatively small cytotoxic T-lymphocyte effector cell pool already in existence in vivo. For this reason, the th

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Koristka, Stefanie, Marc Cartellieri, Anke Theil, et al. "Antigen-Specific Redirection of Human Regulatory T Cells by Bispecific Antibodies,." Blood 118, no. 21 (2011): 4041. http://dx.doi.org/10.1182/blood.v118.21.4041.4041.

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Abstract Abstract 4041 Hematopoietic stem cell transplantation is a commonly used treatment for various hematological malignancies. However, a life-threatening complication following this therapy is the development of Graft versus Host Disease (GvHD), during which transplanted donor immune cells attack the host and lead to severe inflammatory responses and tissue damage. Given the key role of regulatory T cells (Tregs) in immune homeostasis and peripheral tolerance, the adoptive transfer of these cells may represent a promising therapeutic opportunity for the treatment of GvHD. This approach h

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Lin, Tsung-Yi, Jeong A. Park, Alan Long, Hong-Fen Guo, and Nai-Kong V. Cheung. "Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy." Journal for ImmunoTherapy of Cancer 9, no. 9 (2021): e003114. http://dx.doi.org/10.1136/jitc-2021-003114.

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BackgroundThe prognosis for metastatic Ewing sarcoma family of tumors (EFT) is still poor despite high-dose chemotherapy and radiation treatment. Immunotherapies hold promise, but cancer antigen-targeting immunotherapies have largely failed to induce effective T cell receptor-mediated antitumor response. However, T cell-engaging bispecific antibodies (T-BsAbs) have yet to be adequately explored.MethodsRehumanized STEAP1-IgG was used to build T-BsAb (named BC261) using the 2+2 IgG-[L]-scFv platform carrying the anti-CD3 huOKT3 scFv as the second specificity. Its binding epitope mapping, species

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Santich, Brian H., Jeong A. Park, Hoa Tran, Hong-Fen Guo, Morgan Huse, and Nai-Kong V. Cheung. "Interdomain spacing and spatial configuration drive the potency of IgG-[L]-scFv T cell bispecific antibodies." Science Translational Medicine 12, no. 534 (2020): eaax1315. http://dx.doi.org/10.1126/scitranslmed.aax1315.

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T cell–bispecific antibodies (BsAbs) couple cytotoxic T lymphocytes to tumor cells, inducing their destruction. Although there are more than 60 classes of BsAbs in development, the relative importance of parameters such as interdomain spacing or spatial configuration is largely unknown. Here, we dissected a symmetric dual bivalent BsAb platform (IgG-[L]-scFv: antitumor IgG with anti-CD3 scFv fused to the light chains) to explore the importance of valency and spatial configuration for BsAb-induced T cell cytotoxicity. Our results revealed that placing tumor and T cell binding domains on the sam

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Poussin, Mathilde, Arlene Sereno, Xiufeng Wu, et al. "Dichotomous impact of affinity on the function of T cell engaging bispecific antibodies." Journal for ImmunoTherapy of Cancer 9, no. 7 (2021): e002444. http://dx.doi.org/10.1136/jitc-2021-002444.

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BackgroundBispecific T cell engagers represent the majority of bispecific antibodies (BsAbs) entering the clinic to treat metastatic cancer. The ability to apply these agents safely and efficaciously in the clinic, particularly for solid tumors, has been challenging. Many preclinical studies have evaluated parameters related to the activity of T cell engaging BsAbs, but many questions remain.Main bodyThis study investigates the impact of affinity of T cell engaging BsAbs with regards to potency, efficacy, and induction of immunomodulatory receptors/ligands using HER-2/CD3 BsAbs as a model syst

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12

Lindhofer, H., H. Menzel, W. Gunther, L. Hultner, and S. Thierfelder. "Bispecific antibodies target operationally tumor-specific antigens in two leukemia relapse models." Blood 88, no. 12 (1996): 4651–58. http://dx.doi.org/10.1182/blood.v88.12.4651.bloodjournal88124651.

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Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukem

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Martini, Silvia, Mariangela Figini, Aurora Croce, et al. "Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody." Cells 9, no. 10 (2020): 2231. http://dx.doi.org/10.3390/cells9102231.

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Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3+ T cells to kill TRAIL-R2-expressing TNBC cells. In the present study, we investigated whet

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Ruf, Peter, and Horst Lindhofer. "Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody." Blood 98, no. 8 (2001): 2526–34. http://dx.doi.org/10.1182/blood.v98.8.2526.

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Abstract Bispecific antibodies (bsAbs) can efficiently mediate tumor cell killing by redirecting preactivated or costimulated T cells to disseminated tumor cells, especially in a minimal residual disease situation. This study demonstrates that the trifunctional bsAb BiLu is able to kill tumor cells very efficiently without any additional costimulation of effector cells in vitro and in vivo. Remarkably, this bsAb also induces a long-lasting protective immunity against the targeted syngeneic mouse tumors (B16 melanoma and A20 B-cell lymphoma, respectively). A strong correlation was observed betw

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Mhibik, Maissa, Erika M. Gaglione, Amy Blackburn, et al. "A CD19/CD3 Bispecific Antibody Induces Superior T Cell Responses Against Chronic Lymphocytic Leukemia When Combined with Ibrutinib." Blood 134, Supplement_1 (2019): 2861. http://dx.doi.org/10.1182/blood-2019-126186.

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Targeting B-cell receptor signaling with ibrutinib, the first-in-class irreversible inhibitor of Bruton tyrosine kinase, has become a highly successful treatment modality for Chronic Lymphocytic Leukemia (CLL) patients. However, there remains a need for adjunct treatments to deepen responses and prevent or treat resistant disease. Ibrutinib also inhibits inducible T-cell kinase (ITK) which is hypothesized to improve antitumor T-cell immunity. We developed a CD19/CD3 bispecific antibody (bsAb) in a 100 kDa single chain-Fv-Fc format (19/3-scFv-Fc). We previously reported increased T-cell activat

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Kuwahara, Atsushi, Keisuke Nagai, Takeshi Nakanishi, Izumi Kumagai, and Ryutaro Asano. "Functional Domain Order of an Anti-EGFR × Anti-CD16 Bispecific Diabody Involving NK Cell Activation." International Journal of Molecular Sciences 21, no. 23 (2020): 8914. http://dx.doi.org/10.3390/ijms21238914.

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Bispecific antibodies (bsAbs) have emerged as promising therapeutics. A bispecific diabody (bsDb) is a small bsAb consisting of two distinct chimeric single-chain components, with two possible arrangements of the domains. We previously reported the effect of domain order on the function of a humanized bsDb targeting the epidermal growth factor receptor (EGFR) on cancer cells, and CD3 on T cells. Notably, the co-localization of a T-cell receptor (TCR) with CD3 is bulky, potentially affecting the cross-linking ability of bsDbs, due to steric hindrance. Here, we constructed and evaluated humanize

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Kauer, Joseph, Sebastian Hörner, Lukas Osburg, et al. "Tocilizumab, but not dexamethasone, prevents CRS without affecting antitumor activity of bispecific antibodies." Journal for ImmunoTherapy of Cancer 8, no. 1 (2020): e000621. http://dx.doi.org/10.1136/jitc-2020-000621.

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Bispecific antibodies (bsAb) and chimeric antigen receptor (CAR) T cells allow for antibody guided recruitment of T cells against tumors. Both are successfully used for treatment of CD19 expressing leukemias, but may cause cytokine release syndrome (CRS) as a major dose-limiting side effect. For CRS prevention, steroids are recommended prior to bsAb treatment, despite their well-known lymphotoxic activity. The IL-6 receptor antibody tocilizumab is established for treatment of CRS induced by CAR T cells, but was not considered for CRS prevention in bsAb therapy. We here compared the influence o

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Hoseini, Sayed Shahabuddin, Mallika Vadlamudi, Madelyn Espinosa-Cotton, et al. "T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia." Journal for ImmunoTherapy of Cancer 9, no. 5 (2021): e002509. http://dx.doi.org/10.1136/jitc-2021-002509.

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BackgroundAcute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies target the membrane distal immunoglobulin V (IgV) domain of the CD33 extracellular domain.MethodsIn this manuscript, we present data on three bispecific antibodies (BsAbs) against the CD33 IgV and membrane proximal immunoglobulin C (IgC) domains. We use in vitro binding and cytotoxicity assays to show the

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Buelow, Ben, Priya Choudhry, Starlynn Clarke, et al. "Development of a fully human t-cell engaging bispecific antibody for the treatment of multiple myeloma." Journal of Clinical Oncology 36, no. 5_suppl (2018): 60. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.60.

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60 Background: T-cell engaging bispecific antibody (T-BsAb) therapies are highly efficacious and well suited for targets with low expression on tumor cells. Recently, T-BsAbs with high activation of CD3 have been shown to overstimulate T cells, leading to toxicity and decreased efficacy. Teneobio has developed a fully human BCMA-specific T-BsAb using a low-activating αCD3 that is highly effective in vitro and in vivo against MM but stimulates minimal cytokine release. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by Ab repertoire s

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Park, Jeong A., Hong Xu, Brian Santich, and Nai-Kong V. Cheung. "Exceptionally Potent Cytotherapy Using T Cells Armed with Novel Tetravalent Recombinant Bispecific Antibodies Specific for GD2 and HER2." Blood 132, Supplement 1 (2018): 4536. http://dx.doi.org/10.1182/blood-2018-99-120210.

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Abstract Introduction: T-cell based therapies have emerged as one of the major breakthroughs in anticancer treatment: Immune checkpoint inhibitors, chimeric antigen receptor gene-modified T-cells (CAR-T-cells), and T-cell engaging bispecific antibodies (BsAb) are leading the advances. In the era of personalized medicine, T-cells offer alternative strategies to overcome resistance to chemotherapy or small molecules. Yet, hurdles for such therapy can be crippling, such as inability of T cells to infiltrate "cold tumors", cytokine release syndrome following T cell-based therapies, neurologic toxi

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Kauer, Joseph, Fabian Vogt, Ilona Hagelstein, et al. "CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies." Cancers 13, no. 18 (2021): 4596. http://dx.doi.org/10.3390/cancers13184596.

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T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulatin

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Chen, Jie, Zhidi Pan, Lei Han, et al. "A Novel Bispecific Antibody Targeting CD3 and Lewis Y with Potent Therapeutic Efficacy against Gastric Cancer." Biomedicines 9, no. 8 (2021): 1059. http://dx.doi.org/10.3390/biomedicines9081059.

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Lewis Y antigen, a glycan highly expressed on most epithelial cancers, was targeted for cancer treatment but lacked satisfactory results in some intractable and refractory cancers. Thus, it is highly desirable to develop an effective therapy against these cancers, hopefully based on this target. In this work, we constructed a novel T cell-engaging bispecific antibody targeting Lewis Y and CD3 (m3s193 BsAb) with the IgG-[L]-scfv format. In vitro activity of m3s193 BsAb was evaluated by affinity assay to target cells, cytotoxicity assay, cytokines releasing assay, and T cells proliferation and r

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Sivaganesh, Vignesh, Nazifa Promi, Salma Maher, and Bela Peethambaran. "Emerging Immunotherapies against Novel Molecular Targets in Breast Cancer." International Journal of Molecular Sciences 22, no. 5 (2021): 2433. http://dx.doi.org/10.3390/ijms22052433.

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Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administr

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Heitmann, Jonas S., Martin Pfluegler, Gundram Jung, and Helmut R. Salih. "Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives." Cancers 13, no. 3 (2021): 549. http://dx.doi.org/10.3390/cancers13030549.

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Prostate carcinoma (PC) is the second most common cancer in men. When the disease becomes unresponsive to androgen deprivation therapy, the remaining treatment options are of limited benefit. Despite intense efforts, none of the T cell-based immunotherapeutic strategies that meanwhile have become a cornerstone for treatment of other malignancies is established in PC. This refers to immune checkpoint inhibition (CI), which generally reinforces T cell immunity as well as chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) that stimulate the T cell receptor/CD3-complex and

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Koristka, Stefanie, Marc Cartellieri, Anja Feldmann, et al. "Cytotoxic Activity Of Bispecific Antibody-Redirected Human Regulatory T Cells: Fact Or Artifact." Blood 122, no. 21 (2013): 5430. http://dx.doi.org/10.1182/blood.v122.21.5430.5430.

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Abstract Regulatory T cells (Tregs) play an inevitable role in immune homeostasis by maintaining self-tolerance as well as regulating the magnitude of immune responses against foreign antigens. Over the last few years, the enormous potential of adoptive Treg transfer for treatment of auto- and alloimmunity including Graft-versus-Host disease (GvHD) has been validated in a vast number of in vitro and in vivo studies. For their clinical application, all modes of action should be well understood. Regarding their cytotoxic potential, only few and conflicting data exist. On the one hand, it is assu

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Buelow, Ben, Kevin Dang, Pranjali Dalvi, et al. "Effect of modulation of CD3 binding in a PSMAxCD3 T-cell engaging bispecific antibody on maintenance of efficient tumor cell kill and cytokine release." Journal of Clinical Oncology 38, no. 15_suppl (2020): e17583-e17583. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17583.

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e17583 Background: Castration resistant prostate cancer (CRPC) is an incurable disease and represents a significant unmet need. Prostate specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells; expression has been shown to increase with disease progression. Therapies targeting PSMA, such as anti-PSMA radioligand conjugates, have shown promise in clinical trials, validating this target for CRPC. T-cell recruiting bispecific antibodies (T-BsAbs) have demonstrated potent tumor killing activity against multiple tumor types, but immune-mediated toxicit

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Park, Sujeong, Ji-Hae Kim, Yeon-Woo Kang та ін. "450 Combination of rhIL-7-hyFc and anti-PD-L1xCD3ε bispecific antibody enhances antitumor response in mice". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A476—A477. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0450.

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BackgroundrhIL-7-hyFc is a hybrid Fc-fused recombinant human interleukin-7 (NT-I7; efineptakin-alfa) with enhanced bioactivity. In a previous study, we found that a systemic administration of rhIL-7-hyFc induced antitumor effect by increasing CD8+ T cells in the tumor microenvironment. rhIL-7-hyFc monotherapy increased not only PD-1+ tumor-reactive but also intratumoral PD-1- bystander CD8+ T cells. Therefore, we hypothesized that the activation of PD-1- bystander T cells in tumors would enhance the antitumor activity of rhIL-7-hyFc. Here we evaluated the antitumor effect of combination therap

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Robinson, Hannah R., Junpeng Qi, Erika M. Cook, et al. "A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era." Blood 132, no. 5 (2018): 521–32. http://dx.doi.org/10.1182/blood-2018-02-830992.

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Key Points A CD19/CD3 single-chain Fv-Fc bsAb mediated potent killing of CLL cells by autologous T cells in vitro and in vivo. bsAb-mediated cytotoxicity was enhanced by prior therapy with ibrutinib and extended to ibrutinib-resistant disease.

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Buelow, Ben, Brian Avanzino, Aarti Balasubramani та ін. "A CD3 x FRα T-cell engaging bispecific antibody for efficient killing of ovarian cancer cells with minimal cytokine release." Journal of Clinical Oncology 38, № 15_suppl (2020): e18050-e18050. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18050.

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e18050 Background: Ovarian Cancer (OvCa) is the leading cause of gynecologic cancer mortality in women. Since the introduction of platinum-based chemotherapy there has been little change in the prognosis of OvCa patients, with < 30% overall survival in advanced disease, creating an urgent medical need for novel therapies. Few ovarian epithelium-specific surface proteins are suited for Ab targeting. However, studies have shown folate receptor α (FRα) to be highly over-expressed in OvCa; expression level and stage correlate, and FRα is absent or minimally expressed in normal tissues. However,

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Kaneko, T., Y. Fusauchi, Y. Kakui, et al. "A bispecific antibody enhances cytokine-induced killer-mediated cytolysis of autologous acute myeloid leukemia cells." Blood 81, no. 5 (1993): 1333–41. http://dx.doi.org/10.1182/blood.v81.5.1333.1333.

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Abstract An anti-CD3 Fab' x anti-CD13 Fab' bispecific antibody (BsAb) was generated. This BsAb reacted with both CD3+ T cells and CD13+ acute myeloid leukemia (AML) cells. We investigated whether cytokine- stimulated peripheral blood mononuclear cells (PBMC) could lyse patient AML cells after addition of the BsAb. When interleukin-2 (IL-2)- stimulated PBMC were assayed for their cytotoxicity against 51Cr- labeled allogeneic and autologous CD13+ AML cells, their activity was markedly enhanced by the addition of the BsAb. PBMC stimulated with IL- 2 plus anti-CD3 monoclonal antibody (MoAb) showed

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Kaneko, T., Y. Fusauchi, Y. Kakui, et al. "A bispecific antibody enhances cytokine-induced killer-mediated cytolysis of autologous acute myeloid leukemia cells." Blood 81, no. 5 (1993): 1333–41. http://dx.doi.org/10.1182/blood.v81.5.1333.bloodjournal8151333.

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An anti-CD3 Fab' x anti-CD13 Fab' bispecific antibody (BsAb) was generated. This BsAb reacted with both CD3+ T cells and CD13+ acute myeloid leukemia (AML) cells. We investigated whether cytokine- stimulated peripheral blood mononuclear cells (PBMC) could lyse patient AML cells after addition of the BsAb. When interleukin-2 (IL-2)- stimulated PBMC were assayed for their cytotoxicity against 51Cr- labeled allogeneic and autologous CD13+ AML cells, their activity was markedly enhanced by the addition of the BsAb. PBMC stimulated with IL- 2 plus anti-CD3 monoclonal antibody (MoAb) showed higher p

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Honeychurch, Jamie, Alison L. Tutt, Thomas Valerius, Ingmar A. F. M. Heijnen, Jan G. J. Van de Winkel та Martin J. Glennie. "Therapeutic efficacy of FcγRI/CD64-directed bispecific antibodies in B-cell lymphoma". Blood 96, № 10 (2000): 3544–52. http://dx.doi.org/10.1182/blood.v96.10.3544.

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Abstract CD64 (FcγRI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colony-stimulating factor (G-CSF)–activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against immunoglobulin-idiotype (Id), ma

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Honeychurch, Jamie, Alison L. Tutt, Thomas Valerius, Ingmar A. F. M. Heijnen, Jan G. J. Van de Winkel та Martin J. Glennie. "Therapeutic efficacy of FcγRI/CD64-directed bispecific antibodies in B-cell lymphoma". Blood 96, № 10 (2000): 3544–52. http://dx.doi.org/10.1182/blood.v96.10.3544.h8003544_3544_3552.

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CD64 (FcγRI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colony-stimulating factor (G-CSF)–activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against immunoglobulin-idiotype (Id), major histo

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Rovatti, Pier Edoardo, Laura Zito, Eleonora Draghi, et al. "Exploiting an Anti-CD3/CD33 Bispecific Antibody to Redirect Donor T Cells Against HLA Loss Leukemia Relapses." Blood 134, Supplement_1 (2019): 513. http://dx.doi.org/10.1182/blood-2019-126641.

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Background Genomic loss of mismatched HLAs ("HLA loss") represents a frequent modality by which acute myeloid leukemia (AML) evades immune recognition from donor T cells after partially HLA-incompatible allogeneic hematopoietic cell transplantation (allo-HCT). One important consequence of this post-transplantation relapse mechanism is that infusions of lymphocytes from the original donor become ineffectual, prompting the search for alternative therapeutic options. Here, to circumvent the loss of physiological T cell receptor-HLA interactions in these patients, we tested the ability of an anti-

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Arndt, Claudia, Anja Feldmann, Stefanie Koristka, et al. "Redirection of Immune Effector Cells by Bispecific Antibody Systems for the Treatment of Acute Myeloid Leukemia." Blood 118, no. 21 (2011): 1528. http://dx.doi.org/10.1182/blood.v118.21.1528.1528.

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Abstract Abstract 1528 Acute myeloid leukemia (AML) is the most common diagnosed cancer affecting the myeloid line of immune cells in adults. Although chemotherapy initially leads to a remission of the disease in 60–80% of the cases, an enormous number of these patients (50–80%) relapse. Hence, new adjuvant therapeutic strategies for the elimination of minimal residual disease (MRD) are needed. One novel attractive approach is based on recombinant bispecific antibodies (bsAb). BsAb are able to mediate a direct cross-link between T cells and tumor cells. This in turn leads to a polyclonal, MHC-

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Haagen, IA, AJ Geerars, WB de Lau, BJ Bast, and BC de Gast. "The efficacy of CD3 x CD19 bispecific monoclonal antibody (BsAb) in a clonogenic assay: the effect of repeated addition of BsAb and interleukin-2." Blood 85, no. 11 (1995): 3208–12. http://dx.doi.org/10.1182/blood.v85.11.3208.bloodjournal85113208.

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To evaluate the potency by which human T cells are targeted and activated by bispecific monoclonal antibodies (BsAbs) to lyse tumor cells, a clonogenic assay was developed. The efficacy of a CD3 x CD19 BsAb binding to both the CD3 T-cell antigen and the CD19 B-cell antigen was already proven in 51Cr-release assays and in 3-day activation cultures. To achieve more quantitative results, a 14-day clonogenic assay, based on limiting-dilution, was performed for the determination of the initial and residual number of clonogenic units obtained with a CD19+ pre-pre-B acute lymphoblastic leukemia (ALL-

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Arndt, Claudia, Anja Feldmann, Stefanie Koristka, et al. "Improved Killing of AML Blasts By Dual-Targeting of CD123 and CD33 Via Unitarg a Novel Antibody-Based Modular T Cell Retargeting System." Blood 126, no. 23 (2015): 2565. http://dx.doi.org/10.1182/blood.v126.23.2565.2565.

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Abstract Acute myeloid leukemia (AML) is a hematologic malignancy of the myeloid line with high prevalence in older patients. As complete eradication of metastatic cancer cells is often not achieved by standard therapies, alternative treatment modalities are urgently needed. In recent years, bispecific antibodies (bsAbs) and chimeric antigen receptors (CARs) emerged as promising candidates for an antigen-specific cancer immunotherapy. Both bsAbs and CARs are able to redirect T cells for efficient tumor cell lysis. Nevertheless, the development of a novel TAA specific bsAb or a CAR is a long la

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Fournier, Philippe, and Volker Schirrmacher. "Tumor Antigen-Dependent and Tumor Antigen-Independent Activation of Antitumor Activity in T Cells by a Bispecific Antibody-Modified Tumor Vaccine." Clinical and Developmental Immunology 2010 (2010): 1–12. http://dx.doi.org/10.1155/2010/423781.

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New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV—which is obtained by isolation, shortin vitroculture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV)—with bispecific antibodies (bsAbs) binding to this vaccine and introducing anti-CD3 (signal 1) and anti-CD28 (signal 2) antibody activities. This vaccine called ATV-NDV/bsAb sho

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Malik, Harbani, Ben Buelow, Brian Avanzino, et al. "A Novel Fully Human Bispecific CD19 x CD3 Antibody That Kills Lymphoma Cells with Minimal Cytokine Secretion." Blood 132, Supplement 1 (2018): 1671. http://dx.doi.org/10.1182/blood-2018-99-118913.

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Abstract Introduction Along with CD20 and CD22, the restricted expression of CD19 to the B-cell lineage makes it an attractive target for the therapeutic treatment of B-cell malignancies. Many monoclonal antibodies and antibody drug conjugates specific to CD19 have been described, including bispecific T-cell redirecting antibodies (T-BsAbs). In addition, anti-CD19 chimeric antigen receptor T-cells (CAR-Ts) have been approved to treat leukemia. To date, toxicity from over-activation of T-cells and large-scale production of CAR-Ts still hinder this approach. Bispecific T-cell engaging antibodies

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Clarke, Starlynn, Kevin Dang, Yuping Li, et al. "A novel CD3xPSMA bispecific antibody for efficient T cell mediated killing of prostate tumor cells with minimal cytokine release." Journal of Clinical Oncology 37, no. 7_suppl (2019): 324. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.324.

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324 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs p

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Vitale, Laura A., Li-Zhen He, Lawrence J. Thomas, et al. "Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy." Cancer Immunology, Immunotherapy 69, no. 10 (2020): 2125–37. http://dx.doi.org/10.1007/s00262-020-02610-y.

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Abstract CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this ap

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Arndt, Claudia, Marc Cartellieri, Roberta Aliperta, et al. "Enhancing The Efficacy and Specificity Of Antibody-Based T Cell Retargeting Strategies Against Hematological Malignancies." Blood 122, no. 21 (2013): 930. http://dx.doi.org/10.1182/blood.v122.21.930.930.

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Abstract New promising candidates for cancer immunotherapy are bispecific antibodies (bsAbs) which have already shown a convincing anti-tumor effect in first clinical trials. BsAbs are composed of two single-chain fragments variable (scFvs), derived from the variable heavy and light chain of a monoclonal Ab (mAb), which bind to the activating CD3-complex on T cells and a tumor-associated antigen (TAA) on cancer cells. Consequently, the cross-linkage of effector and target cells by bsAbs results in an efficient T cell-mediated cancer cell killing. However, several serious adverse effects were o

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Ellmark, Peter, Karin Hägerbrand, Mattias Levin, et al. "858 A bispecific antibody targeting CD40 and EpCAM induces superior anti-tumor effects compared to the combination of the monospecific antibodies." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A911. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0858.

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BackgroundAlligator has developed a new concept, Neo-X’, to enable antigen presenting cells to efficiently enhance priming of neoantigen-specific T cells, which may be the missing aspect in tumors that lack T cell infiltration. We hypothesize that binding of the CD40 x EpCAM bsAb (4224) to CD40 on DCs and EpCAM on tumor exosomes or tumor debris leads to i) activation of the DC, ii) uptake of the tumor material, iii) cross-presentation of tumor-derived neoantigen (present in exosomes or debris) and iiii) priming of tumor neoantigen-specific T cells, resulting in an increased quantity and/or qua

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Rossi, Diane L., Edmund A. Rossi, David M. Goldenberg, and Chien-Hsing Chang. "A New Platform For Trivalent Bispecific Antibodies Used For T-Cell Redirected Killing Of B-Cell Malignancies." Blood 122, no. 21 (2013): 3078. http://dx.doi.org/10.1182/blood.v122.21.3078.3078.

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Abstract Background Various formats of bispecific antibodies (bsAbs) to redirect effector T cells for the targeted killing of tumor cells have shown considerable promise both pre-clinically and clinically. The scFv-based constructs, including BiTE and DART, which bind monovalently to CD3 on T cells and to the target antigen on tumor cells, exhibit fast blood clearance and neurological toxicity due to their small size (∼55 kDa). Herein, we describe the generation of novel T-cell redirecting trivalent bsAbs comprising an anti-CD3 scFv covalently conjugated to a stabilized F(ab)2. The design was

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Robinson, Hannah R., Junpeng Qi, Sivasubramanian Baskar, et al. "Activity of CD19/CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia." Blood 130, Suppl_1 (2017): 799. http://dx.doi.org/10.1182/blood.v130.suppl_1.799.799.

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Abstract Kinase inhibitors such as ibrutinib have advanced treatment of chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments capable of deepening response or overcoming resistance to kinase inhibitors. CD19/CD3 bispecific antibodies (bsAbs) recruit endogenous T cells to form cytolytic synapses with CD19+ tumor cells. Blinatumomab, a CD19/CD3 bsAb designed in the 54 kDa BiTE format, is FDA approved for the treatment of some forms of acute lymphoblastic leukemia, and has potential for use in other B-cell malignancies. However, due to its short half-life of 2.1

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Park, Jeong A., Hong fen Guo, Hong Xu, and Nai-Kong V. Cheung. "PD-L1 Checkpoint Blockade Augments Anti-Tumor Immune Response of GD2 or HER2-Bsab Ex Vivo Armed T-Cells (EVAT) Therapy in Osteosarcoma." Blood 134, Supplement_1 (2019): 1959. http://dx.doi.org/10.1182/blood-2019-131325.

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Background Ex Vivo Armed T-cells (EVAT) carrying zeptomoles (10-21M) of T-cell engaging GD2-bispecific antibody (GD2-EVAT) or HER2-bispecific antibodies (HER2-EVAT) have potent anti-tumor activity against GD2(+) and/or HER2(+) solid tumors. Strategies to further optimize this approach are highly relevant. PD-1 is a key immune checkpoint receptor expressed mainly by activated T-cells and mediates immune suppression by binding to its ligands PD-L1 or PD-L2. Upregulation of PD-L1 has been found in many cancers including osteosarcoma and associated with aggressive disease and poor outcome. While t

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Groeneveldt, Christianne, Priscilla Kinderman, Diana J. M. van den Wollenberg, et al. "Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy." Journal for ImmunoTherapy of Cancer 8, no. 2 (2020): e001191. http://dx.doi.org/10.1136/jitc-2020-001191.

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BackgroundT-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors.MethodsThe mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-c

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Groeneveldt, Christianne, Priscilla Kinderman, Diana JM van den Wollenberg, et al. "590 Pre-conditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A625. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0590.

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BackgroundThe use of T cell-engaging CD3-bispecific antibodies (CD3-bsAbs) is a promising immunotherapeutic strategy for cancer. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors.1 Oncolytic viruses are emerging as anti-cancer therapeutics, and accumulating evidence demonstrates their applicability to sensitize tumors for immune checkpoint immunotherapy.2 In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silen

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Buelow, Ben, Starlynn Clarke, Kevin Dang, et al. "Evaluation of monovalent versus biparatopic CD3xPSMA bispecific antibodies for t-cell mediated killing of prostate tumor cells with minimal cytokine release." Journal of Clinical Oncology 37, no. 15_suppl (2019): e16519-e16519. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16519.

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e16519 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new treatments are needed. Therapies directed against Prostate specific membrane antigen (PSMA) -such as radiolabeled antibodies, chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs)- have shown promising efficacy but also induce significant toxicity. In particular T-cell redirection leads to efficient killing of tumor cells but induces cytokine release-related toxicities. We have developed a panel of monovalent and biparatopic CD3xPSMA bispecific antibodies

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Hiemstra, Ida H., Patrick J. Engelberts, Bart de Jong, et al. "Duobody-CD3xCD20 Shows Unique and Potent Preclinical Anti-Tumor Activity in Vitro and In Vivo, and Is Being Evaluated Clinically in Patients with B-Cell Malignancies." Blood 132, Supplement 1 (2018): 1664. http://dx.doi.org/10.1182/blood-2018-99-115957.

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Abstract DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 and the B-cell antigen CD20, that triggers potent T-cell-mediated lysis of CD20-expressing cells. DuoBody-CD3xCD20 is a full-length bispecific IgG1 generated by controlled Fab-arm exchange (cFAE) [1, 2] and contains an effector function-silenced Fc region. In vitro, DuoBody-CD3xCD20 induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells, as measured by flow cytometry and bromodeoxyuridine (BrdU) incorporation as

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