ABSTRACT Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that... more ABSTRACT Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.
NTB-A is a CD2-related cell surface protein expressed on lymphoid cells including B-lymphocytes f... more NTB-A is a CD2-related cell surface protein expressed on lymphoid cells including B-lymphocytes from Chronic Lymphocytic Leukemia (CLL) and lymphoma patients. We have generated a series of mAbs against NTB-A and assessed their therapeutic potential in preclinical models. Selected mAbs to NTB-A were further tested in functional Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL and lymphoma patients. Potent cytotoxic activity was demonstrated against B cells isolated from CLL patients and B lymphoma cell lines. Chimeric anti-NTB-A mAbs demonstrated anti-tumor activity equal to rituximab against CA46 human lymphoma xenografts in nude mice at a low dose. In a chimpanzee safety study, a single dose of lead anti-NTB-A mAb 994.1 resulted in near-complete depletion of peripheral lymphocytes while having a minimal effect on T cell activation. Taken together, these results demonstrate NTB...
Key Points PF-06747143, a novel CXCR4 antagonist IgG1 Ab, mobilizes malignant cells from the BM a... more Key Points PF-06747143, a novel CXCR4 antagonist IgG1 Ab, mobilizes malignant cells from the BM and induces their death via Fc-effector function. PF-06747143 reduces tumor burden in NHL, AML, and MM models, both as a monotherapy or in combination with standard-of-care agents.
The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid line... more The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction is fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives and efficacy. It has been hypothesized that 2 FcRn molecules bind an IgG homodimer with disparate affinities, yet their affinity constants are inconsistent across the literature. Using surface plasmon resonance biosensor assays that eliminated confounding experimental artifacts, we present data supporting an alternate hypothesis: 2 FcRn molecules saturate an IgG homodimer with identical affinities at independent sites, consistent with the symmetrical arrangement of the FcRn/Fc complex observed in the crystal structure published by Burmeister et al. in 1994. We find that human FcRn binds human IgG1 with an equilibrium dissociation constant (KD) o...
The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid line... more The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction is fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives and efficacy. It has been hypothesized that 2 FcRn molecules bind an IgG homodimer with disparate affinities, yet their affinity constants are inconsistent across the literature. Using surface plasmon resonance biosensor assays that eliminated confounding experimental artifacts, we present data supporting an alternate hypothesis: 2 FcRn molecules saturate an IgG homodimer with identical affinities at independent sites, consistent with the symmetrical arrangement of the FcRn/Fc complex observed in the crystal structure published by Burmeister et al. in 1994. We find that human FcRn binds human IgG1 with an equilibrium dissociation constant (KD) o...
ABSTRACT Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that... more ABSTRACT Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.
NTB-A is a CD2-related cell surface protein expressed on lymphoid cells including B-lymphocytes f... more NTB-A is a CD2-related cell surface protein expressed on lymphoid cells including B-lymphocytes from Chronic Lymphocytic Leukemia (CLL) and lymphoma patients. We have generated a series of mAbs against NTB-A and assessed their therapeutic potential in preclinical models. Selected mAbs to NTB-A were further tested in functional Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL and lymphoma patients. Potent cytotoxic activity was demonstrated against B cells isolated from CLL patients and B lymphoma cell lines. Chimeric anti-NTB-A mAbs demonstrated anti-tumor activity equal to rituximab against CA46 human lymphoma xenografts in nude mice at a low dose. In a chimpanzee safety study, a single dose of lead anti-NTB-A mAb 994.1 resulted in near-complete depletion of peripheral lymphocytes while having a minimal effect on T cell activation. Taken together, these results demonstrate NTB...
Key Points PF-06747143, a novel CXCR4 antagonist IgG1 Ab, mobilizes malignant cells from the BM a... more Key Points PF-06747143, a novel CXCR4 antagonist IgG1 Ab, mobilizes malignant cells from the BM and induces their death via Fc-effector function. PF-06747143 reduces tumor burden in NHL, AML, and MM models, both as a monotherapy or in combination with standard-of-care agents.
The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid line... more The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction is fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives and efficacy. It has been hypothesized that 2 FcRn molecules bind an IgG homodimer with disparate affinities, yet their affinity constants are inconsistent across the literature. Using surface plasmon resonance biosensor assays that eliminated confounding experimental artifacts, we present data supporting an alternate hypothesis: 2 FcRn molecules saturate an IgG homodimer with identical affinities at independent sites, consistent with the symmetrical arrangement of the FcRn/Fc complex observed in the crystal structure published by Burmeister et al. in 1994. We find that human FcRn binds human IgG1 with an equilibrium dissociation constant (KD) o...
The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid line... more The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction is fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives and efficacy. It has been hypothesized that 2 FcRn molecules bind an IgG homodimer with disparate affinities, yet their affinity constants are inconsistent across the literature. Using surface plasmon resonance biosensor assays that eliminated confounding experimental artifacts, we present data supporting an alternate hypothesis: 2 FcRn molecules saturate an IgG homodimer with identical affinities at independent sites, consistent with the symmetrical arrangement of the FcRn/Fc complex observed in the crystal structure published by Burmeister et al. in 1994. We find that human FcRn binds human IgG1 with an equilibrium dissociation constant (KD) o...
Uploads
Papers by Ishita Barman