A Cancer-Specific Monoclonal Antibody against HER2 for Breast Cancers

Abstract

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is an important target for monoclonal antibody (mAb) therapy such as trastuzumab. All therapeutic mAbs, including anti-HER2 mAbs, exhibit adverse effects probably due to the recognition of antigens expressed in normal cells. Therefore, tumor-selective or specific mAbs have been desired to reduce adverse effects. In this study, we provide a strategy for the selection of cancer-specific mAb against HER2. We screened more than 200 of anti-HER2 mAbs obtained by our laboratory and established a novel cancer-specific anti-HER2 antibody, H2Mab-250 (IgG1, kappa). H2Mab-250 reacted with HER2-positive breast cancer BT-474 and SK-BR-3 cells. Importantly, H2Mab-250 never showed reactivity to non-transformed normal epithelial cells (HaCaT and MCF 10A) and immortalized normal epithelial cells in flow cytometry. In contrast, most anti-HER2 mAbs including H2Mab-119 (IgG1, kappa) reacted with both cancer and normal epithelial cells. The epitope mapping revealed that H2Mab-250 recognized the domain VI of HER2 and the Trp614 mainly contributes to the recognition by H2Mab-250. In immunohistochemical analysis, H2Mab-250 exhibited a superior reactivity to HER2-positive breast cancer section compared to H2Mab-119. Importantly, H2Mab-250 never showed any reactivity to normal tissues by immunohistochemical analysis. The strategy to select cancer-specific mAbs would contribute to the development of novel antibodies and modalities for cancer therapy.

Antitumor activities against breast cancers by an afucosylated anti‐HER2 monoclonal antibody H2Mab‐77‐mG2a‐f

“…61 When used in conjunction with trastuzumab, the HER2-targeted humanized mAb 1E11 inhibits the growth of HER2-expressing gastric tumors by binding to the HER2 domain IV, which does not overlap with trastuzumab. 62 68 and H 2 Mab-250 69 are anti-HER2 mAbs that we have previously established, and some of them were proved to have antitumor effects. 48,63 In our early findings, these mAbs have different epitopes, including HER2 domains I, III, and IV.…”

“… 62 Therefore, one of the primary strategies for combating drug resistance is the development of antibodies with a variety of features, including the binding epitope. H 2 Mab‐19, 63 H 2 Mab‐41, 64 H 2 Mab‐77, 38 H 2 Mab‐119, 65 H 2 Mab‐139, 66 H 2 Mab‐181, 67 H 2 Mab‐214, 68 and H 2 Mab‐250 69 are anti‐HER2 mAbs that we have previously established, and some of them were proved to have antitumor effects. 48 , 63 In our early findings, these mAbs have different epitopes, including HER2 domains I, III, and IV.…”

Defucosylated Monoclonal Antibody (H2Mab-139-mG2a-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2

“…Anti-PDPN-CasMabs are currently applied to CAR-T therapy in preclinical models [43,44]. For the development of anti-HER2 CasMab, we need to perform further screening of our already established anti-HER2 mAbs (more than 200 clones), comparing their reactivity against normal cells [45,46]. Anti-HER2 CasMabs could be employed in designing modalities including ADCs and CAR-T.…”

A Humanized and Defucosylated Antibody against Podoplanin (humLpMab-23-f) Exerts Antitumor Activities in Human Lung Cancer and Glioblastoma Xenograft Models

“…We successfully applied a PDPN-targeting CasMab to chimeric antigen receptor (CAR)-T therapy in mice preclinical studies of human glioblastoma [20]. Recently, we further developed anti-HER2 CasMabs [21].…”