Abstract
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). 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 sequentially to one of five dose-escalation cohorts of AME-133v at 2, 7.5, 30, 100, or 375 mg/m(2) weekly × 4 doses. AME-133v showed a 13- to 20-fold greater binding affinity for CD20 and was 5- to 7-fold more potent than rituximab in ADCC assays. Cell binding assays showed AME-133v and rituximab competed for an overlapping epitope on the CD20 antigen, and AME-133v inhibited binding of biotinylated rituximab to CD20 in a concentration-dependent manner. AME-133v was well tolerated by patients and common related adverse events included chills and fatigue. One patient experienced a dose-limiting toxicity of neutropenia. AME-133v showed nonlinear pharmocokinetics with properties similar to rituximab. Selective reduction of B cells during and after AME-133v treatment was shown by flow cytometry of peripheral blood. A partial or complete response was observed in 5 of 23 (22%) patients and the median progression-free survival was 25.4 weeks. AME-133v was safe and well tolerated at the doses tested. AME-133v showed encouraging results as an anti-CD20 therapy in heavily pretreated FL patients with the less favorable FcγRIIIa F-carrier genotype.
Highlights
Rituximab is effective as monotherapy or in combination with chemotherapy in patients with follicular lymphomaAuthors' Affiliations: 1University of Alabama at Birmingham, Birmingham, Alabama; 2David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California; 3Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio; 4Eli Lilly and Company, Indianapolis, Indiana; 5Eli Lilly and Company, Windlesham, United Kingdom; 6University of Florida, Gainseville, Florida; 7Applied Molecular Evolution, San Diego, California; 8Fox Chase Cancer Center, Philadelphia, Pennsylvania; 9Holden Comprehensive Cancer Center at University of Iowa, Iowa City, Iowa; and 10Stanford University Cancer Center, Palo Alto, CaliforniaNote: Supplementary data for this article are available at Clinical Cancer Research Online.Ó2012 American Association for Cancer Research.(FL; ref. 1)
Competitive binding experiments were carried out to determine whether AME-133v and rituximab bound to the same epitope on the CD20 antigen expressed on SKW6.4 B cells
The nonspecific competitor immunoglobulin G1 (IgG1) at 150 mg/mL had no effect upon the binding of rituximab even after 32-hour incubation; in the presence of AME-133v, a time-dependent reduction in rituximab binding signal was observed, with most of the biotinylated rituximab being competed from the cells within 32 hours
Summary
Rituximab is effective as monotherapy or in combination with chemotherapy in patients with follicular lymphomaAuthors' Affiliations: 1University of Alabama at Birmingham, Birmingham, Alabama; 2David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California; 3Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio; 4Eli Lilly and Company, Indianapolis, Indiana; 5Eli Lilly and Company, Windlesham, United Kingdom; 6University of Florida, Gainseville, Florida; 7Applied Molecular Evolution, San Diego, California; 8Fox Chase Cancer Center, Philadelphia, Pennsylvania; 9Holden Comprehensive Cancer Center at University of Iowa, Iowa City, Iowa; and 10Stanford University Cancer Center, Palo Alto, CaliforniaNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2012 American Association for Cancer Research.(FL; ref. 1). A single-nucleotide polymorphism (SNP) in the FcgRIIIa gene that results in a valine at amino acid position-158 in both alleles (158-VV), rather than a phenylalanine in at least one allele (158-VF or –FF; F-carrier), leads to a CD16a on immune effector cells with higher affinity for immunoglobulin G1 (IgG1) monoclonal antibodies (mAb), including rituximab [4]. An optimized CD20 antibody was more effective at activating natural killer (NK) cells, a surrogate for ADCC, than rituximab or CD20 antibodies modified to have only higher affinity for CD20 [5, 6]. The greatest improvement in NK cell activation was noted in the presence of effector cells from FcgRIIIa F-carrier donors; the fully optimized CD20 antibody activated www.aacrjournals.org
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