MacroGenics is developing margetuximab (or MGAH22), a next-generation, Fc-optimized monoclonal antibody (mAb) that targets HER2. Based on an observation that different genotypes of FcγR within the patient population lead to different durations of progression-free survival, the company has optimized the Fc region of the antibody to markedly increase binding to the low affinity allele of FcγR. The intent is to reduce population differences related to FcγR genotype (see figure below) in responses of patients with HER2-expressing tumors. Such tumors potentially include breast, bladder, gastric, prostate and pancreatic.
Based on results from its Phase 1 clinical study of margetuximab, MacroGenics has initiated a Phase 2 clinical trial in a population of patients with metastatic breast cancer whose tumors express a moderate level of the oncoprotein, HER2, represented by a 2+ score by immunohistochemistry. These tumors must also lack evidence of HER2 gene amplification as determined by FISH testing. The trial is being conducted at six sites across the United States.
The HER2 oncoprotein is overexpressed and plays an important role in tumorigenesis, tumor aggressiveness, and outcome in breast cancer and other solid tumors. HER2 has proven to be an excellent target for cancer therapeutics with the clinical success of the monoclonal antibody, trastuzumab. The benefits of trastuzumab therapy, however, accrue exclusively to patients with HER2 3+, or gene-amplified, breast tumors. Thus, therapies are needed for patients whose tumors over-express the HER2 oncoprotein at the <3+ levels without gene amplification. A number of other human tumors over-express HER2, albeit not as frequently or exuberantly as does breast cancer and usually in the absence of gene amplification. Trastuzumab is not indicated for these patients.
Rationale for the Development of MGAH22
Trastuzumab is believed to mediate its therapeutic activity against HER2-positive tumors by a combination of mechanisms, including promoting modulation of the receptor (internalization and/or “shedding”), induction of apoptosis, antibody-mediated cellular cytotoxicity (ADCC), and presentation of the antigenic determinants of opsonized cells to antigen-presenting cells. A recent study by Musolino, et al. (J Clin Oncol 2008) expands to trastuzumab (see figure below), a well-established observation in the field of therapeutic antibodies, previously seen with rituximab, infliximab, and cetuximab. This study demonstrates that the polymorphic variants of the activating low-affinity Fcγ receptors expressed in metastatic breast cancer patients predict response duration to trastuzumab. Patients homozygous for the FcγRIIIA (CD16A) 158V variant and/or for the FcγRIIA (CD32A) 131H variant have longer progression-free survival than patients carrying the 158F or 131R variants. The CD16A polymorphism was the greater predictor of response duration, while CD32A-131H was associated with a favorable trend. Importantly, both 158V and 131H variants bind the Fc of IgG1, the main class of therapeutic mAbs listed above, with higher affinity than their allelic counterparts. This is consistent with observations that FcγR-mediated mechanisms play a critical part in the action of these antibodies (Clynes, Nat Med 2000). Because only about 15-20% of all individuals are homozygous for the high-binding alleles of CD16A (or CD32A), only a minority of the patient population will fully benefit from this intervention. These data represent a strong rationale for engineering the Fc domain of therapeutic IgG1 mAbs to interact with the low-binding alleles of the activating Fc receptors with increased affinity in order to expand the full benefit potential to all patients independently of their FcR allotype.