Annals of oncology : official journal of the European Society for Medical Oncology, Apr 24, 2017
Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and hig... more Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1 - 6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10 - 18 mg/kg) (Regimen B). Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as p...
T-cell directed killing of tumor cells using bispecific antibodies is a promising approach for th... more T-cell directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a Dual Affinity Re-targeting (DART) molecule generated from antibodies to CD3 and CD123 which is designed to redirect T cells against acute myeloid leukemia blasts. The CD3xCD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of one antibody in tandem with the VL of the other antibody. The target antigen CD123 (IL3RA) is highly and differentially expressed in AML blasts compared to normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD3xCD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3xCD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These res...
Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may ... more Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be rapidly cleared, and therefore requires continuous delivery. In a mouse model of continuous administration, MGD006 eliminated engrafted KG-1a cells (an AML-M0 line) in human PBMC (peripheral blood mononuclear cell)-reconstituted NSG/β2m(-/-) mice at doses as low as 0.5 μg/kg per day for ~7 days. MGD006 binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells. MGD006 was well tolerated in monkeys continuousl...
Background Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vac... more Background Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vaccines over the past 20 years. Serotype replacement, limited efficacy for certain vaccine serotypes, and the incomplete coverage of disease in the elderly perpetuate the problem. Novel vaccines with broader serotype coverage are needed. To this end, a novel 24-valent pneumococcal vaccine, ASP3772, was developed based on a multiple antigen-presenting system (MAPS) platform. This platform takes advantage of the high affinity, noncovalent binding between biotin and rhizavidin to create a complex of 24 pneumococcal polysaccharides and a fusion of two pneumococcal proteins. Methods Healthy adults aged 18-64 years were randomized into this active-controlled, observer-blinded, dose-escalation study to evaluate the safety, tolerability, and immunogenicity of ASP3772 at three dose levels compared to Prevnar13 (PCV13) (target 30 per dose group). The primary endpoints were safety and reactogenicity....
T-cell directed killing of tumor cells using bispecific reagents is a promising approach for the ... more T-cell directed killing of tumor cells using bispecific reagents is a promising approach for the treatment of hematologic malignancies. In contrast to B-cell malignancies, this approach has been limited in AML by the lack of tumor-specific antigens/targets. CD123 (IL3RA) is highly and differentially expressed in AML blasts compared to normal hematopoietic stem and progenitor cells and is a potential target for immunotherapy. We investigated the ability of a DART constructed from an antibody to CD123 (7G3) and a MacroGenics’ proprietary CD3 antibody to redirect T cells against CD123+ AML blasts. DARTs consist of 2 independent polypeptides, each comprising the VH of one antibody in tandem with the VL of the other antibody. The resultant heterodimer is stabilized by a disulfide bond at the carboxyl terminal domains of the 2 VH regions. This construct binds to both the N-terminal extracellular domain of human CD123 and to the extracellular domain of CD3 in the human T-cell receptor comp...
Annals of oncology : official journal of the European Society for Medical Oncology, Apr 24, 2017
Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and hig... more Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1 - 6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10 - 18 mg/kg) (Regimen B). Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as p...
T-cell directed killing of tumor cells using bispecific antibodies is a promising approach for th... more T-cell directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a Dual Affinity Re-targeting (DART) molecule generated from antibodies to CD3 and CD123 which is designed to redirect T cells against acute myeloid leukemia blasts. The CD3xCD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of one antibody in tandem with the VL of the other antibody. The target antigen CD123 (IL3RA) is highly and differentially expressed in AML blasts compared to normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD3xCD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3xCD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These res...
Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may ... more Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be rapidly cleared, and therefore requires continuous delivery. In a mouse model of continuous administration, MGD006 eliminated engrafted KG-1a cells (an AML-M0 line) in human PBMC (peripheral blood mononuclear cell)-reconstituted NSG/β2m(-/-) mice at doses as low as 0.5 μg/kg per day for ~7 days. MGD006 binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells. MGD006 was well tolerated in monkeys continuousl...
Background Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vac... more Background Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vaccines over the past 20 years. Serotype replacement, limited efficacy for certain vaccine serotypes, and the incomplete coverage of disease in the elderly perpetuate the problem. Novel vaccines with broader serotype coverage are needed. To this end, a novel 24-valent pneumococcal vaccine, ASP3772, was developed based on a multiple antigen-presenting system (MAPS) platform. This platform takes advantage of the high affinity, noncovalent binding between biotin and rhizavidin to create a complex of 24 pneumococcal polysaccharides and a fusion of two pneumococcal proteins. Methods Healthy adults aged 18-64 years were randomized into this active-controlled, observer-blinded, dose-escalation study to evaluate the safety, tolerability, and immunogenicity of ASP3772 at three dose levels compared to Prevnar13 (PCV13) (target 30 per dose group). The primary endpoints were safety and reactogenicity....
T-cell directed killing of tumor cells using bispecific reagents is a promising approach for the ... more T-cell directed killing of tumor cells using bispecific reagents is a promising approach for the treatment of hematologic malignancies. In contrast to B-cell malignancies, this approach has been limited in AML by the lack of tumor-specific antigens/targets. CD123 (IL3RA) is highly and differentially expressed in AML blasts compared to normal hematopoietic stem and progenitor cells and is a potential target for immunotherapy. We investigated the ability of a DART constructed from an antibody to CD123 (7G3) and a MacroGenics’ proprietary CD3 antibody to redirect T cells against CD123+ AML blasts. DARTs consist of 2 independent polypeptides, each comprising the VH of one antibody in tandem with the VL of the other antibody. The resultant heterodimer is stabilized by a disulfide bond at the carboxyl terminal domains of the 2 VH regions. This construct binds to both the N-terminal extracellular domain of human CD123 and to the extracellular domain of CD3 in the human T-cell receptor comp...
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Papers by Gurunadh Chichili