Abstract
The anti-ErbB2 antibodies trastuzumab and pertuzumab in combination have recently been approved for the treatment of patients with ErbB2-positive metastatic breast cancer. Pertuzumab, which binds to ErbB2 near the center of domain II, and trastuzumab, which binds to the juxtamembrane region of ErbB2 domain IV, directly interfere with domain II- and domain IV-mediated heterodimerization contacts, respectively. In this study, we report a novel anti-ErbB2 antibody, 3E10, which binds to an epitope in domain III that appears to be located opposite to the dimerization interfaces in domain II and domain IV of ErbB2. Our data show that the 3E10 antibody inhibits ErbB2 heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab. It could be speculated that the 3E10 antibody may affect ErbB2 heterodimerization by causing major conformational changes of ErbB2. Furthermore, 3E10 provides synergistic inhibition of ErbB2 heterodimerization and signaling in combination with either trastuzumab or pertuzumab. The combination of these three anti-ErbB2 antibodies that have complementary mechanisms of action appears to be an extremely potent ErbB2 heterodimerization blocker. Compared with trastuzumab plus pertuzumab, the combination of trastuzumab, pertuzumab and 3E10 provides a more potent blockade of ErbB2 signaling. Consistent with this, trastuzumab plus pertuzumab plus 3E10 results in greater in vitro and in vivo antitumor activity in ErbB2-overexpressing breast tumor models, suggesting its potential use for treating ErbB2-overexpressing breast cancer.
Highlights
Overexpression of human epidermal growth factor receptor-2(HER2 or ErbB2), a member of the ErbB family of receptor tyrosine kinases, is found in 25–30% of human breast cancers, and correlates with more aggressive tumors and a poorer prognosis.[1,2]Trastuzumab, a humanized monoclonal antibody directed against ErbB2, is the first anti-ErbB2 treatment approved for clinical use for patients with ErbB2-overexpressing metastatic breast cancer.[3]
We report an ErbB2 domain III-specific antibody, which inhibits heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab
The combination of trastuzumab, pertuzumab and C3E10 has superior antitumor activity compared with trastuzumab plus pertuzumab We investigated the effects of the combination of C3E10 with trastuzumab and pertuzumab on ErbB2 heterodimerization (Figures 4a and b)
Summary
(HER2 or ErbB2), a member of the ErbB family of receptor tyrosine kinases, is found in 25–30% of human breast cancers, and correlates with more aggressive tumors and a poorer prognosis.[1,2]. In the absence of ErbB3 ligand, the abilities of these two antibodies to inhibit ErbB2/ErbB3 heterodimer formation are reversed.[8] The combination of these two anti-ErbB2 antibodies that have complementary mechanisms of action synergistically inhibits the in vitro and in vivo growth of ErbB2-overexpressing breast cancer cell lines.[16,17] Recently, trastuzumab plus pertuzumab has been approved for the treatment of patients with ErbB2-overexpressing metastatic breast cancer. We report an ErbB2 domain III-specific antibody, which inhibits heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab. The combination of the three anti-ErbB2 antibodies that have different mechanisms of action exhibits superior efficacy over the combination of trastuzumab and pertuzumab
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