Research ArticleCancer

p95HER2–T cell bispecific antibody for breast cancer treatment

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaat1445
DOI: 10.1126/scitranslmed.aat1445

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Fine-tuning HER2 targeting

HER2 receptor tyrosine kinase is frequently overexpressed in breast and gastric cancer. HER2-overexpressing tumors can be treated with trastuzumab, an antibody against this receptor, and additional methods of targeting HER2 are also being developed. Unfortunately, HER2 is also expressed in normal tissues, resulting in unacceptable toxicities when HER2-targeting therapies damage healthy organs. Rius Ruiz et al. now propose targeting p95HER2, a carboxyl-terminal fragment of HER2 that is expressed in almost half of HER2-positive tumors. The authors demonstrate the effectiveness of this approach, as well as its safety due to the lack of p95HER2 expression in nontumor tissues.

Abstract

T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to tumor-associated or tumor-specific antigens. The receptor tyrosine kinase HER2 is a tumor-associated antigen in ~25% of breast cancers. TCBs targeting HER2 may result in severe toxicities, likely due to the expression of HER2 in normal epithelia. About 40% of HER2-positive tumors express p95HER2, a carboxyl-terminal fragment of HER2. Using specific antibodies, here, we show that p95HER2 is not expressed in normal tissues. We describe the development of p95HER2-TCB and show that it has a potent antitumor effect on p95HER2-expressing breast primary cancers and brain lesions. In contrast with a TCB targeting HER2, p95HER2-TCB has no effect on nontransformed cells that do not overexpress HER2. These data pave the way for the safe treatment of a subgroup of HER2-positive tumors by targeting a tumor-specific antigen.

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