Results of a Phase 1 Study of AME-133v (LY2469298), an Fc-Engineered Humanized Monoclonal Anti-CD20 Antibody, in FcγRIIIa-Genotyped Patients with Previously Treated Follicular Lymphoma
Abstract:Purpose: AME-133v is a humanized monoclonal antibody engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab. Safety, pharmacokinetics, and efficacy were assessed in a phase 1/2 trial in patients with previously treated follicular lymphoma (FL).Patients and Methods: AME-133v was characterized in vitro by ADCC and cell binding assays. A phase 1 study was conducted in which 23 previously treated patients with FL were assigned sequential… Show more
“…In two Phase 1 clinical studies for patients with previously treated follicular lymphoma, ocaratuzumab was well tolerated at all doses tested. 8,11 Ocaratuzumab demonstrated a dose-dependent, rapid, and specific depletion of the B cells in all patients receiving at least 7.5mg/m 2 of the mAb. 8 Clinical activity was seen with response rates of 22-50% in these studies, 8,11 even in patients previously treated with rituximab.…”
Section: Introductionmentioning
confidence: 93%
“…8 In preclinical studies completed with SKW6.4 lymphoma cell line and primary B-lymphocytes, ocaratuzumab demonstrated a 13-to 20-fold increase in binding affinity for CD20 compared with rituximab. Additionally, ocaratuzumab was approximately 6-fold more potent than rituximab in ADCC assays.…”
Section: Introductionmentioning
confidence: 99%
“…Additionally, ocaratuzumab was approximately 6-fold more potent than rituximab in ADCC assays. 8 In monkey models, ocaratuzumab in i.v. and AME-133E (a closely related antibody) in subcutaneous (s.c.) formulation showed tolerability and dose-dependent B cell depletion.…”
“…In two Phase 1 clinical studies for patients with previously treated follicular lymphoma, ocaratuzumab was well tolerated at all doses tested. 8,11 Ocaratuzumab demonstrated a dose-dependent, rapid, and specific depletion of the B cells in all patients receiving at least 7.5mg/m 2 of the mAb. 8 Clinical activity was seen with response rates of 22-50% in these studies, 8,11 even in patients previously treated with rituximab.…”
Section: Introductionmentioning
confidence: 93%
“…8 In preclinical studies completed with SKW6.4 lymphoma cell line and primary B-lymphocytes, ocaratuzumab demonstrated a 13-to 20-fold increase in binding affinity for CD20 compared with rituximab. Additionally, ocaratuzumab was approximately 6-fold more potent than rituximab in ADCC assays.…”
Section: Introductionmentioning
confidence: 99%
“…Additionally, ocaratuzumab was approximately 6-fold more potent than rituximab in ADCC assays. 8 In monkey models, ocaratuzumab in i.v. and AME-133E (a closely related antibody) in subcutaneous (s.c.) formulation showed tolerability and dose-dependent B cell depletion.…”
“…13-to 20-fold greater binding affinity for CD20 than rituximab. 60 The Fc region has been modified to improve affinity for FcγRIIIa-158F and -158V genotypes. As a result, AME-133v shows greater in vitro activation of natural killer cells and 5-to 7-fold more potent ADCC than rituximab.…”
Section: Type I Cd20 Antibodiesmentioning
confidence: 99%
“…Recent work with TNFR agonistic antibodies including CD40 and DR5 antibodies has shown that binding to CD40 and FcγRIIb in cis is required to mediate potent CD40 or DR5 activation. [83][84][85] We propose that Type I CD20 antibodies bind to CD20 on B cells in a conformation that allows simultaneous binding to FcγRIIb on the same cell (in cis) resulting in crosslinking, FcγRIIb co-activation and CD20 co-internalization upon binding potentially in lipid rafts. Vice versa, the biological effects could be explained by the different binding conformation of Type II CD20 antibodies that might prevent simultaneous binding in cis to FcγRIIB, which precludes FcγRIIb crosslinking and CD20 co-internalization (Fig.…”
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