Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties

Breast Cancer Res. 2011;13(6):R123. doi: 10.1186/bcr3069. Epub 2011 Nov 30.


Introduction: Response to trastuzumab in metastatic breast cancer correlates with expression of the high binding variant (158V) of the activating Fcγ receptor IIIA (CD16A). We engineered MGAH22, a chimeric anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab, with an Fc domain engineered for increased binding to both alleles of human CD16A.

Methods: MGAH22 was compared to an identical anti-HER2 mAb except for a wild type Fc domain. Antibody-dependent cell cytotoxicity (ADCC) assays were performed with HER2-expressing cancer cells as targets and human PBMC or purified NK cells as effectors. Xenograft studies were conducted in mice with wild type murine FcγRs; in mice lacking murine CD16; or in mice lacking murine CD16 but transgenic for human CD16A-158F, the low-binding variant. The latter model reproduces the differential binding between wild type and the Fc-optimized mAb for human CD16A. The JIMT-1 human breast tumor line, derived from a patient that progressed on trastuzumab therapy, was used in these studies. Single and repeat dose toxicology studies with MGAH22 administered intravenously at high dose were conducted in cynomolgus monkeys.

Results: The optimized Fc domain confers enhanced ADCC against all HER2-positive tumor cells tested, including cells resistant to trastuzumab's anti-proliferative activity or expressing low HER2 levels. The greatest improvement occurs with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding allele. MGAH22 demonstrates increased activity against HER2-expressing tumors in mice transgenic for human CD16A-158F. In single and repeat-dose toxicology studies in cynomolgus monkeys, a species with a HER2 expression pattern comparable to that in humans and Fcγ receptors that exhibit enhanced binding to the optimized Fc domain, MGAH22 was well tolerated at all doses tested (15-150 mg/kg) and exhibited pharmacokinetic parameters similar to that of other anti-HER2 antibodies. Induction of cytokine release by MGAH22 in vivo or in vitro was similar to that induced by the corresponding wild type mAb or trastuzumab.

Conclusions: The data support the clinical development of MGAH22, which may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / toxicity
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibody-Dependent Cell Cytotoxicity
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Neoplasms / metabolism
  • Protein Binding
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / metabolism
  • Receptors, IgG / metabolism*
  • Trastuzumab


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • FCGR3A protein, human
  • Receptors, IgG
  • Receptor, ErbB-2
  • Trastuzumab