Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab
- 3 September 2005
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 55 (6), 717-727
- https://doi.org/10.1007/s00262-005-0058-x
Abstract
Dimerization is essential for activity of human epidermal growth factor receptors (HER1/EGFR, HER2/ErbB2, HER3/ErbB3, and ErbB4) and mediates intracellular signaling events leading to cancer cell proliferation, survival, and resistance to therapy. HER2 is the preferred dimerization partner. Activation of HER signaling pathways may be blocked by inhibition of dimer formation using a monoclonal antibody (MAb) directed against the dimerization domain of HER2. The murine MAb 2C4 that specifically binds the HER2 dimerization domain was cloned as a chimeric antibody, humanized using a computer-generated model to guide framework substitutions, and variants were tested as Fabs. Pharmacokinetics and toxicology were evaluated in rodents and cynomolgus monkeys. Cloning the variable domains of MAb 2C4 into a vector containing human kappa and CH1 domains allowed construction of a mouse-human chimeric Fab. DNA sequencing of the chimeric clone permitted identification of CDR residues. The full-length IgG1 of variant F-10 was equivalent in binding to chimeric IgG1 and was designated pertuzumab (rhuMAb 2C4; Omnitarg). Pertuzumab pharmacokinetics was best described by a two-compartment model with a distribution phase of <1 day, terminal half-life of ~10 days, and volume of distribution of ~40 mL/kg that approximates serum volume. With the exception of diarrhea, pertuzumab was generally well tolerated in cynomolgus monkeys. Pertuzumab, a recombinant humanized IgG1 MAb, is the first of a new class of agents known as HER dimerization inhibitors. Inhibition of HER dimerization may be an effective anticancer strategy in tumors with either normal or elevated expression of HER2.This publication has 37 references indexed in Scilit:
- Phase I Clinical Study of Pertuzumab, a Novel HER Dimerization Inhibitor, in Patients With Advanced CancerJournal of Clinical Oncology, 2005
- Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung CancerJournal of Clinical Oncology, 2004
- Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complexCancer Cell, 2004
- The ErbB receptors and their role in cancer progressionExperimental Cell Research, 2003
- Structure of the extracellular region of HER2 alone and in complex with the Herceptin FabNature, 2003
- Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning MutagenesisJournal of Molecular Biology, 2002
- ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signalingThe EMBO Journal, 1997
- Framework Residues 71 and 93 of the Chimeric B72.3 Antibody are Major Determinants of the Conformation of Heavy-chain Hypervariable LoopsJournal of Molecular Biology, 1995
- X-ray Structures of the Antigen-binding Domains from Three Variants of Humanized anti-p185HER2 Antibody 4D5 and Comparison with Molecular ModelingJournal of Molecular Biology, 1993
- Framework residue 71 is a major determinant of the position and conformation of the second hypervariable region in the VH domains of immunoglobulinsJournal of Molecular Biology, 1990