Journal Publication: First-Generation & Preclinical Evaluation of an EphA5-Targeted ADC in Solid Tumors

Introduction

Nonspecific, cytotoxic, drug-based systemic chemotherapy remains the foundation of most treatment regimens for a broad range of cancers. These agents, however, have very low therapeutic indices and often generate severe side effects, thereby restricting their effective use in patients with cancer. In contrast, antibody-drug conjugate (ADC) agents utilize a targeting monoclonal antibody (mAb) component to deliver cytotoxic payloads directly to cancer cells, thereby sparing normal tissues. Only five cancer-specific targets have thus far been approved by the FDA for ADC-based therapy against solid tumors: human epidermal growth factor receptor 2 (1, 2), human trophoblast cell surface glycoprotein antigen 2 (TROP2) (3, 4), tissue factor (5, 6), nectin cell adhesion molecule 4 (nectin-4) (7, 8), and folate receptor α (9, 10). Therefore, the discovery and validation of new molecular targets for ADC applications constitute a promising strategy to advance cancer biology and the emerging field of targeted cancer therapy.

Here we report the receptor tyrosine kinase EphA5 as a highly selective target for directed anticancer therapy (11, 12). We demonstrate that EphA5 is expressed in many human solid tumors, including aerodigestive tract tumors (non–small cell lung [NSCLC], head and neck, gastric, colon, and pancreatic cancers), genitourinary tract tumors (bladder and ovarian cancers), and most subsets of breast tumors (including triple-negative cancer). In contrast, EphA5 displays no or limited expression in normal human tissues.

MBrace Therapeutics designed, generated, and developed MBRC-101, a first-in-class targeted ADC against EphA5, and conducted a comprehensive preclinical program of efficacy and Good Laboratory Practice (GLP) toxicology to support investigational testing in human patients with cancer. MBRC-101 is an ADC composed of a humanized anti-EphA5 antibody conjugated to a monomethyl auristatin E (MMAE). MBRC-101 uses the clinically validated valine-citrulline cleavable linker and Abzena’s proprietary ThioBridge disulfide rebridging conjugation technology to form a homogeneous ADC with four drug molecules per antibody (drug/antibody ratio of 4 [DAR4]). MBRC-101 was highly active when tested in patient-derived xenograft (PDX) models of human cancer expressing moderate to high levels of EphA5, potently regressing tumor xenografts relative to controls in all experimental designs. Toxicologic evaluation in rats and non-human primates showed that MBRC-101 is well-tolerated with dose-proportional toxicokinetics. Collectively, these results demonstrate that EphA5 is a viable molecular target for the development of mAb-based therapies, and that MBRC-101 has many key attributes of a promising ADC candidate for the treatment of human solid tumors

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