Abstract 2581: Development of an Fc-domain-optimized monoclonal antibody with enhanced potency against HER2-expressing tumors

Abstract

Abstract Polymorphic variants of the activating Fcγ receptors (FcγR) expressed in metastatic breast cancer patients predict response duration to trastuzumab [Musolino J Clin Oncol 26:1789 2008]. Patients homozygous for the 158V variant of FcγRIIIA (CD16A) have longer progression-free survival than those carrying the 158F variant. CD16A-158V binds the Fc domain of IgG1 with higher affinity than CD16A-158F. Because <20% of all individuals are CD16A-158V homozygous, only a minority of the patient population will fully benefit from trastuzumab treatment. Furthermore, the benefit of trastuzumab only accrues to patients whose tumor is “addicted” to HER2 overexpression, with no perceived benefit to those expressing HER2 at the ≤2+ level without gene amplification. MGAH22 is a human/mouse chimeric IgG1 anti-HER2 monoclonal antibody (mAb) that has been engineered to increase the affinity of the Fc domain for both CD16A alleles and decrease the affinity for the inhibitory receptor, FcγRIIB (CD32B). MGAH22 maintains the anti-proliferative activity of the parental mAb (4D5, the precursor to trastuzumab) and exhibits improved antibody-dependent cell cytotoxicity (ADCC) compared to an identical mAb with a wild type Fc domain. The greatest improvement in ADCC activity was observed on low HER2-expressing target cells and with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding CD16A allele. MGAH22 also exhibited enhanced antitumor activity against a trastuzumab-resistant HER2+ tumor (JIMT-1) in xenograft experiments conducted in mice transgenic for human CD16A-158F. In a repeat-dose toxicology study in cynomolgus monkeys, there were no test article-related findings except for non-adverse dose-independent reductions in circulating natural killer (NK) cells that were not accompanied by decreased NK cell cytolytic activity. A transient induction of serum IL-6 levels occurred within 4 hours of infusion with MGAH22 or, to a lesser extent, vehicle. The terminal half-life of MGAH22 in cynomolgus monkeys was approximately 7 to 9 days and the NOAEL was determined to be 150 mg/kg. These data support the clinical development of MGAH22 as a treatment of HER2-positive cancers, particularly in CD16A-158F carriers. Patients that may benefit from treatment with MGAH22 include: (i.) breast cancer patients whose tumors overexpress HER2 at the 2+ level and do not exhibit gene amplification, (ii.) breast cancer patients whose tumors overexpress HER2 and have progressed on trastuzumab therapy and (iii.) patients with certain other solid tumors that overexpress the HER2 oncoprotein at the 2+ or 3+ level and for whom trastuzumab therapy has not been demonstrated to be beneficial. A Phase 1 dose escalation study to assess MGAH22 in patients with HER2-positive tumors is expected to initiate in 2010. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2581.