Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Abstract

Trastuzumab resistance is a common problem that impedes the effectiveness of trastuzumab in ErbB2-amplified cancers. About 70% of ErbB2-amplified breast cancers do not respond to trastuzumab (de novo resistance), and the majority of the trastuzumab-responsive cancers progress within 1 year (acquired resistance). Different mechanisms exist between de novo and acquired resistance. Innate resistance mechanisms are mainly independent of ErbB2 receptor activity, and acquired resistance involves with alterations depending on ErbB2 activity. We previously reported H2-18, an ErbB2 domain I-specific antibody, which could circumvent de novo resistance to trastuzumab. Here, we modeled the development of acquired resistance by treating human gastric cancer cell line NCI-N87 with trastuzumab to obtain the trastuzumab-resistant subline, NCI-N87-TraRT. Next, we investigated the antitumor efficacy of H2-18 in NCI-N87-TraRT cell line. H2-18 exhibited a significantly greater antitumor activity in NCI-N87-TraRT tumor-bearing nude mice than pertuzumab and trastuzumab, either alone or in combination. The unique ability of H2-18 to overcome acquired resistance may be attributable to its potent programmed cell death-inducing activity, which was probably mediated by RIP1-ROS-JNK-c-Jun pathway. In conclusion, H2-18 may have the potential as an effective agent to circumvent acquired resistance to trastuzumab in ErbB2-overexpressing cancers.

Synergistic antitumor effect of the anti‑ErbB2 antibodies trastuzumab and H2‑18 on trastuzumab‑resistant gastric cancer cells

“…The anti-ErbB2 antibodies trastuzumab and pertuzumab and the anti-CD20 antibody rituximab were expressed and purified by a similar method described in previous studies (20)(21)(22). The drug concentrations used in the present experiments and the ratio of anti-ErbB2 antibodies in antibody combinations were based on previous experiments (13,23).…”

“…Despite cancer progression on ErbB2-directed therapies (9)(10)(11)(12), ErbB2 remains considered as a valid therapeutic target. Pertuzumab is another anti-ErbB2 (human) antibody, that binds to an epitope of ErbB2 different from trastuzumab (9,13). Among the strategies to overcome trastuzumab resistance, the combination of pertuzumab and trastuzumab has provided clinical benefits (9,13).…”

“…Pertuzumab is another anti-ErbB2 (human) antibody, that binds to an epitope of ErbB2 different from trastuzumab (9,13). Among the strategies to overcome trastuzumab resistance, the combination of pertuzumab and trastuzumab has provided clinical benefits (9,13). However, the objective response rate is 24.2% and the complete response rate is ~8% (9).…”

“…In previous studies, an ErbB2 domain I-specific human antibody, H2-18, was developed, which exhibited a more potent antitumor activity than trastuzumab and pertuzumab, either alone or in combination, in trastuzumab-resistant breast and gastric cancer cells (13,18). H2-18 functions by potently inducing programmed cell death (PCD), a different mechanism of action from either trastuzumab or pertuzumab (13,18). Therefore, it was speculated that the two anti-ErbB2 antibodies, H2-18 and trastuzumab, which have different mechanisms of action, may also achieve a synergistic effect on the inhibition of trastuzumab-resistant cancer.…”

Theranostic Pretargeting Drug Delivery and Imaging Platforms in Cancer Precision Medicine

“…Breast cancer is the most prevalent malignancy in women in the United States, and ~20–30% of human BrCa overexpress HER2 receptors, a molecular marker that correlates with cancer aggressiveness, metastasis, and poor prognosis. HER2-overexpressing BrCa are treated with the humanized anti-HER2 monoclonal antibody, Trastuzumab (Tz), which is highly efficacious, but unfortunately, trastuzumab resistance develops over long-term use ( 31 – 33 ). Trastuzumab-based ADC, T-DM1, was developed for treatment of resistant tumors by directly conjugating the chemotherapeutic drug, mertansine, on the antibody to boost cytotoxicity ( 34 ).…”