A Novel HER3-Targeting Antibody–Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization

Abstract

Purpose: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models.Experimental Design: In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patientderived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys.Results: U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys.Conclusions: U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3mediated payload delivery via high internalization into tumor cells.

Kinase drug discovery 20 years after imatinib: progress and future directions

“…Proof of clinical concept has already been achieved with approvals of anti-HER2 ADCs, such as trastuzumab–emtansine (T-DM1) and trastuzumab–deruxtecan (T-DXd) for breast cancer 217 , 218 , in which the anti-HER2 is linked to a cytotoxic microtubule inhibitor and a topoisomerase 1 inhibitor, respectively. Similarly, patritumab, a HER3 antibody linked to DXd (HER3–DXd) is in early clinical development for the treatment of solid tumours such as colorectal cancer 219 .…”

Antibody–drug conjugates in solid tumors: a look into novel targets

“…In NSCLC, HER3-overexpression has been reported in 80% of EGFR-mutated adenocarcinomas [78]. HER3-DXd demonstrated to inhibit tumor growth in HER3+, EGFRmutated, EGFR-TKI resistant patient-derived xenograft (PDX) models, while it was ineffective in HER3-negative models [79]. A phase I trial then investigated this ADC in EGFR-mutated NSCLC progressing to first generation EGFR-TKIs and negative for T790M mutation, or after osimertinib failure [80].…”

Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model

“…Additionally, differences in the internalization rate were observed for the studied variants in a panel of cell lines with varying levels of HER3 expression. The ability to induce rapid internalization is of relevance when designing payload delivery, which could be a viable strategy for HER3-targeted therapy [25]. Based on our results, we hypothesized that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on tumor targeting, biodistribution properties, and internalization rates.…”