Home » Key Drug Discovery Articles » Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance

Pedersen MW1, Jacobsen HJ2, Koefoed K2, Dahlman A2, Kjær I2, Poulsen TT2, Meijer PJ2, Nielsen LS2, Horak ID2, Lantto J2, Kragh M2.

Mol Cancer Ther. 2015 Jan 22.

1Symphogen A/S, Ballerup, Denmark. [email protected] and

2Symphogen A/S, Ballerup, Denmark.

 

Abstract

HER2 plays an important role in the development and maintenance of the malignant phenotype of several human cancers. As such, it is a frequently pursued therapeutic target and two antibodies targeting HER2 have been clinically approved, trastuzumab and pertuzumab. It has been suggested that optimal inhibition of HER2 is achieved when utilizing two or more antibodies targeting nonoverlapping epitopes. Superior clinical activity of the trastuzumab plus pertuzumab combination in metastatic breast cancer supports this hypothesis. Because trastuzumab and pertuzumab were not codeveloped, there may be potential for further optimizing HER2 targeting. The study herein evaluated functional activity of anti-HER2 antibody combinations identifying optimal epitope combinations that provide efficacious HER2 inhibition. High-affinity antibodies to all four extracellulardomains on HER2 were identified and tested for ability to inhibit growth of different HER2-dependent tumor cell lines. An  antibody mixture targeting three HER2 subdomains proved to be superior to  trastuzumab, pertuzumab, or a combination in vitro and to trastuzumab in two in vivo models. Specifically, the tripartite antibody mixture induced efficient HER2 internalization and degradation demonstrating increased sensitivity in cell lines with HER2 amplification and high EGFR levels. When compared with individual and clinically approved mAbs, the synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anticancer activity. Mol Cancer Ther; 14(3); 1-12. ©2015 AACR.

©2015 American Association for Cancer Research.

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Figure legend

Model illustrating how a three mAb mixture binding non-overlapping epitopes on HER2 might lead to superior anti-tumor control. The three mAb mixture induces HER2 degradation by receptor cross-linking and at the same time prevent compensatory heterodimerization with EGFR and/or HER3. Resulting in effective shutdown of HER2 mediated signaling and ultimately superior inhibition of HER2 dependent cancer cells.

HER-2 mechanism of Sym005 action

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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