The Experts below are selected from a list of 332580 Experts worldwide ranked by ideXlab platform

Polly Matzinger - One of the best experts on this subject based on the ideXlab platform.

  • spontaneous mutation in the CD79b gene leads to a block in b lymphocyte development at the c early pre b stage
    Genes and Immunity, 2009
    Co-Authors: Natalia Shulzhenko, Andrey Morgun, Polly Matzinger
    Abstract:

    We discovered B-lymphocyte-deficient mice within a group of B10.A-CD45.1 mice, and established that this deficiency was a recessively inherited trait. Gene mapping and sequence analysis showed a mutation in the third exon of the CD79b gene (c.224G>A) that leads to the generation of a stop codon (W75X) in the mutant mouse. Fluorescent-activated cell sorting analysis of bone marrow cells showed that the mutant mice did not express the CD79b Antigen. To establish where the block in development happens, we analyzed CD43posB220pos B-lymphocyte precursors present in the mutant mice and found that the fraction C′ (corresponding to early pre-B lymphocytes) was absent in the mutant mouse, whereas fractions B and C showed a relative accumulation. As expected, we found no IgG or IgA in mutant mice. These results suggest that this CD79b-mutant strain may be a useful tool for immunological research in human immunodeficiencies.

  • Spontaneous mutation in the CD79b gene leads to a block in B-lymphocyte development at the C′ (early pre-B) stage
    Genes and Immunity, 2009
    Co-Authors: Natalia Shulzhenko, Andrey Morgun, Polly Matzinger
    Abstract:

    We discovered B-lymphocyte-deficient mice within a group of B10.A-CD45.1 mice, and established that this deficiency was a recessively inherited trait. Gene mapping and sequence analysis showed a mutation in the third exon of the CD79b gene (c.224G>A) that leads to the generation of a stop codon (W75X) in the mutant mouse. Fluorescent-activated cell sorting analysis of bone marrow cells showed that the mutant mice did not express the CD79b Antigen. To establish where the block in development happens, we analyzed CD43posB220pos B-lymphocyte precursors present in the mutant mice and found that the fraction C′ (corresponding to early pre-B lymphocytes) was absent in the mutant mouse, whereas fractions B and C showed a relative accumulation. As expected, we found no IgG or IgA in mutant mice. These results suggest that this CD79b-mutant strain may be a useful tool for immunological research in human immunodeficiencies.

Siddharth Sukumaran - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3628 t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • Abstract 3628: T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

Yvonne Chen - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3628 t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • Abstract 3628: T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • pre clinical characterization of t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Arthur E Reyes, Yvonne Chen, Eric Stefanich
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

  • Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Yvonne Chen, Arthur E Reyes
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

Diego Ellerman - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3628 t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • Abstract 3628: T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • pre clinical characterization of t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Arthur E Reyes, Yvonne Chen, Eric Stefanich
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

  • Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Yvonne Chen, Arthur E Reyes
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

Mary Mathieu - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3628 t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • Abstract 3628: T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies
    Cancer Research, 2017
    Co-Authors: Peiyin Wang, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Christoph Spiess, Cecile Chalouni, Robyn Clark, Yvonne Chen, Jessica Li, Siddharth Sukumaran
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. We have adopted a knobs-into-holes antibody format and produced T-cell dependent bispecific antibodies (TDB), as full length, humanized IgG1 antibodies with natural antibody architecture, which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex, which has been clinically validated by an anti-CD79b antibody-drug conjugate (ADC) as a safe and effective therapeutic target for B cell malignancies (Leukemia 2015 Pfeifer et.al). In the present work, we show that anti-CD79b/CD3 TDB is active against lymphoma cells with a wide range of CD79b Antigen levels in vitro. In addition, anti-CD79b/CD3 TDB appears to be insensitive to the status of cellular signaling pathways in lymphoma cells as it is active against cell lines that are resistant to the BTK inhibitor ibrutinib or an anti-CD79b ADC with a cleavable tubulin inhibitor as the payload. In vivo, anti-CD79b/CD3 TDB administration inhibited tumor growth in B-cell lymphoma xenograft models and resulted in potent B-cell depletion in the blood and spleens in a humanized murine model. To assess the safety of targeting CD79b with a T-cell recruiting bispecific antibody in non-human primates, a surrogate anti-cynoCD79b/CD3 TDB with comparable in vitro potency was produced with a target arm that recognizes cynomolgus monkey CD79b and the same anti-CD3 arm. In a single dose pharmacokinetic/pharmacodynamics/safety study, anti-cynoCD79b/CD3 TDB administration at 1mg/kg resulted in potent B cell depletion, as well as T cell activation and proliferation, which was assessed by flow cytometry on blood and lymphoid tissue and immunohistochemistry on lymphoid tissue. The pharmacokinetic properties of anti-cynoCD79b/CD3 TDB resembled that of IgG antibodies; though with a faster clearance likely due to CD79b Antigen internalization and enhanced binding to CD3 when compared to previously described anti-CD20/CD3 TDB. Transient cytokine release was observed as elevated levels of IL-2, IL-6, IFN-gamma and TNF-alpha were detected within 24 hours following administration. Anti-cynoCD79b/CD3 TDB was well-tolerated in the majority of dosed animals without toxicologically significant findings. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB can be a potential therapeutic agent in B cell malignancies. Citation Format: Peiyin Wang, Maria Hristopoulos, Robyn Clark, Yvonne Chen, Diego Ellerman, Mary Mathieu, Christoph Spiess, Jessica Li, Cecile Chalouni, Siddharth Sukumaran, Eric Stefanich, Jeffrey Wallin, Robert Li, Tanja Zabka, Klara Totpal, Mark Dennis, Allen Ebens, Stephen Gould, Andrew Polson, Liping Laura Sun. T cell-dependent bispecific antibody anti-CD79b/CD3 as a potential therapy for B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3628. doi:10.1158/1538-7445.AM2017-3628

  • pre clinical characterization of t cell dependent bispecific antibody anti CD79b cd3 as a potential therapy for b cell malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Arthur E Reyes, Yvonne Chen, Eric Stefanich
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.

  • Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies
    Blood, 2014
    Co-Authors: Xiaocheng Chen, Andrew Polson, Mark S Dennis, Diego Ellerman, Clarissa Johnson, Mary Mathieu, Amy Oldendorp, Yvonne Chen, Arthur E Reyes
    Abstract:

    T-cell recruiting bispecific antibodies and antibody fragments have been used to harness the cytotoxic potential of T cells for cancer treatment. As an example, encouraging clinical responses have been reported with the B cell targeting Blinatumomab, a 55-kDa fusion protein composed of two single-chain antibody fragments (scFvs). However, the therapeutic promise of many reported bispecific antibodies and fragments is often limited by unfavorable pharmacokinetics and administration schedule, immunogenicity, and a propensity towards aggregation. We have adopted a knobs-into-holes (KIH) antibody format and produced T-cell dependent bispecific antibodies (TDB), which allow one arm to target various B cell Antigens while the other arm recruits T cells by binding to the CD3e subunit of the T-cell receptor. These B cell targeting TDBs are full length, humanized IgG1 antibodies with natural antibody architecture. Single dose pharmacokinetic/pharmacodynamic studies in cynomolgus monkeys show the KIH format TDBs are well tolerated in life, result in potent B cell depletion in peripheral and lymphoid tissue, and demonstrate pharmacokinetic properties resembling conventional antibody therapy. One B cell Antigen targeted is CD79b, a component of the B cell receptor complex. CD79b is restricted to B cells, is highly prevalent on B cell leukemia and lymphomas, and has been clinically validated by an anti-CD79b antibody-drug conjugate as a safe and effective therapeutic target for B cell malignancies (ASCO 2014 abstract#8519). In our present work, we show that anti-CD79b/CD3 TDB can be produced and purified from E.coli, free of homodimer and aggregates. Anti-CD79b/CD3 TDB is a conditional agonist, activating CD3+T cells only in the presence of CD79b expressing B cells. In vitro, it induces potent B cell killing in a T-cell dependent manner, and is broadly active against lymphoma cell lines with a wide range of CD79b Antigen levels. Compared to bispecific antibodies targeting some other B cell Antigens, anti-CD79b/CD3 TDB appears to be more potent in autologous B cell killing assays with human PBMCs isolated from healthy donors. Taking advantage of antibodies with a range of binding affinities, we show that the B cell cytotoxic potency of anti-CD79b/CD3 TDB can be enhanced with increased binding affinity of either the anti-CD79b arm or the anti-CD3 arm in vitro. To assess the therapeutic potential of anti-CD79b/CD3 TDB, we further demonstrate that it is active in killing B lymphoma cells isolated from leukemia and lymphoma patients. Collectively, these preclinical data suggest anti-CD79b/CD3 TDB may be a promising agent for clinical development in B cell malignancies. Disclosures Sun:Genentech: Employment. Chen:Genentech: Employment. Chen:Genentech: Employment. Dennis:Genentech: Employment. Ellerman:Genentech: Employment. Johnson:Genentech: Employment. Mathieu:Genentech: Employment. Oldendorp:Genentech: Employment. Polson:Genentech: Employment. Reyes:Genentech: Employment. Stefanich:Genentech: Employment. Wang:Genentech: Employment. Wang:Genentech: Employment. Zheng:Genentech: Employment. Ebens:Genentech: Employment.