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posted on 2025-09-02, 07:26 authored by Sagun Parakh, Nhi Huynh, Diana Dong Cao, Angela Rigopoulos, Benjamin Gloria, Ingrid J.G. Burvenich, Carmel Murone, Christian W. Wichmann, Nancy Yanan Guo, Clare Senko, Adam Parslow, Laura Allan, Laura D. Osellame, Peter W. Janes, Fiona E. Scott, Zhanqi Liu, Hui K. Gan, Andrew M. Scott <p>The effect of mAb104, trastuzumab and pertuzumab monotherapy (left) or in combination (right) on the growth of (A) NCI-N87, (B) BT-474, (C) SK-BR-3 and (D) OE-19 in-vitro as measured by MTS assay. Cells were incubated with antibodies or isotype control in serum-depleted media for 5-7 days. The number of viable cells determined at baseline and at end of experiment. Results are presented as Mean ± SD, n = 3. Data is representative of two or more independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001 vs isotype control.</p>
Funding
National Health and Medical Research Council (NHMRC)
Victorian Cancer Agency (VCA)
History
ARTICLE ABSTRACT
We generated a novel HER2 mAb104, which binds to an epitope in domain II of HER2 that is conformationally exposed in tumors in response to HER2 amplification or activation but is not accessible to antibody binding in normal tissues. Consistent with other studies that evaluated antibodies targeting conformationally exposed epitopes, mAb104 lacked in vitro activity but showed potent antitumor activity in vivo. The antitumor effect in vivo was similar in magnitude to trastuzumab and pertuzumab, and combination with trastuzumab was superior to trastuzumab alone. IHC screening of normal and tumor tissues with mAb104 showed that mAb104 did not bind to normal tissues, confirming the tumor specificity of mAb104. In vivo biodistribution and imaging data demonstrated specific tumor targeting of mAb104 in HER2-expressing tumors. Confocal microscopy clearly demonstrated the internalization of mAb104 into the tumor cells, consistent with mAb104:HER2 trafficking. mAb104 is tumor-specific, exhibits potent antitumor activity in HER2-positive models, and internalizes into HER2-positive tumor cells. These results demonstrate the potential of mAb104 as a novel HER2-targeting therapy, both as a naked antibody for signaling abrogation therapy and for payload delivery as an antibody–drug conjugate or for β/α particle therapy.
