A Novel Anti-HER2 Antibody–Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine

Abstract

Most patients with HER2-positive breast or gastric cancer exhibit primary or acquired resistance to trastuzumab emtansine (T-DM1), and such patients may have limited therapeutic options. XMT-1522 is a novel anti-HER2 antibody-drug conjugate. We compared XMT-1522 to T-DM1 in preclinical models. The effects of XMT-1522 and T-DM1 on cell survival and apoptosis were compared in six HER2-positive breast cancer or gastric cancer cell lines, of which three lines were T-DM1-sensitive (N-87, OE-19, JIMT-1) and three T-DM1resistant (RN-87, ROE-19, SNU-216). We compared these agents also in the HER2-negative breast cancer cell line MCF-7, and in mouse RN-87 and JIMT-1 xenograft models. Cell survival was assessed using the AlamarBlue method and apoptosis with the Caspase-Glo 3/7 method. XMT-1522 inhibited the growth of all six HER2-positive cell lines. The proportions of cells that survived XMT-1522 treatment were smaller as compared with T-DM1, particularly in the T-DM1resistant cell lines. XMT-1522 induced more cell apoptosis compared with T-DM1. While RN-87 and JIMT-1 xenograft tumors progressed on T-DM1 treatment, all tumors responded to XMT-1522, and all but one tumor disappeared during the XMT-1522 treatment. XMT-1522 had a strong antitumor effect on RN-87 and JIMT-1 xenografts that progressed on T-DM1. We conclude that XMT-1522 was effective in HER2-positive breast cancer and gastric cancer cell lines resistant to T-DM1, and in xenograft models resistant to T-DM1. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer.

Combination efficacy of pertuzumab and trastuzumab for trastuzumab emtansine-resistant cells exhibiting attenuated lysosomal trafficking or efflux pumps upregulation

“…As third-line therapy, the continuous use of a HER-targeting drug, such as TRAS or lapatinib, with chemotherapy has been reported to prolong progression-free survival in patients [16,17]; however, data on the selection of anti-HER2 drugs in patients with T-DM1 resistance are lacking and require clarification. Recently, several possible mechanisms of T-DM1 resistance have been reported: (1) reduced binding of T-DM1 to HER2 by HER2 downregulation [18] or by mucin 4 (MUC4) [19]; (2) attenuation of AKT signal inhibition caused by phosphatase and tensin homolog (PTEN) loss [20]; (3) signaling via the EGFR [21]; (4) overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters that are involved in multidrug resistance [18,20,22]; (5) downregulation of the lysosomal transporter solute carrier family 46 member 2 (SLC46A2) [20,23], lysosomal metabolic disorders [24,25], or abnormal lysosomal trafficking [26]; or (6) altered microtubule dynamics through a mutation in tubulin or altered activation of mitotic regulators [27,28]. Except for (1)-(3), these resistance mechanisms are specific to T-DM1 and not to TRAS or PER.…”

ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer

“…Despite a lower drug to antibody ratio, ARX788 showed superior anti-cancer efficacy in our breast cancer and gastric cancer models. The T-DM1-resistant RN-87 and ROE-19 cells express high amounts of ABC transporters (ABCC1, ABCC2, and ABCG2) [19], and the expression of these proteins was higher in the T-DM1resistant than in the T-DM1-sensitive N87 xenografts ( Supplementary Fig. 4).…”

“…In accordance with these findings, we observed lower expression of HER2 on the T-DM1-resistant RN-87 and ROE-19 gastric cancer cells as compared to their sensitive counterparts. In addition, the T-DM1-resistant RN-87 and ROE-19 cells have higher ABC transporter expression than the sensitive N-87 and OE-19 cells [19]. A complete loss of HER2 expression caused acquired T-DM1-resistance in an in vitro model using JIMT-1 breast cancer cells [26].…”

“…4). The inhibition of ABC transporters sensitizes the resistant cells to T-DM1 [19] indicating that ABC transporters may play an important role in the T-DM1-resistance of these cells. Yet, these cells were highly sensitive to ARX788, suggesting that pAF-AS269 may be a less avid substrate for ABCC1, ABCC2, and/or ABCG2 than lysine-MCC-DM1, the active metabolite of T-DM1, but this hypothesis requires further study.…”

“…The cell lines were cultured according to the recommended specifications. The T-DM1-resistant HER2-positive gastric cancer cell lines RN-87 and ROE-19 were generated in our laboratory by treating the N-87 and OE-19 cells, respectively, with increasing concentrations of T-DM1 (Roche Ltd., Basel, Switzerland) as described previously [19]. Authentication of the cell lines was performed using a short tandem repeat analysis.…”