First-generation and preclinical evaluation of an EphA5-targeted antibody-drug conjugate in solid tumors

Abstract

Contemporary cancer treatment strategies are shifting toward targeted therapies to improve efficacy and minimize toxicity. Here, we report the design and preclinical evaluation of MBRC-101, a first-in-class antibody-drug conjugate (ADC) targeting EphA5, a receptor tyrosine kinase with an established role in embryonic development but not extensively studied in cancer. We show that EphA5 is expressed in multiple solid tumors, including cancers of the aerodigestive (non–small cell lung, head and neck, gastric, colon, and pancreatic) and genitourinary (bladder and ovary) tracts, as well as most breast cancer subsets (including triple-negative tumors), with limited expression in normal tissues.

MBRC-101 is a humanized anti-EphA5 antibody conjugated to monomethyl auristatin E (MMAE) through  Abzena’s ThioBridge conjugation technology, thereby ensuring a stable drug-to-antibody ratio and reducing off-target effects. MBRC-101 showed potent antitumor activity, achieving complete tumor regression in several patient-derived xenograft models. Preclinical Good Laboratory Practice–compliant toxicology studies in rats and nonhuman primates demonstrated that MBRC-101 is well tolerated, with observed toxicities limited to known MMAE off-target effects. These findings establish EphA5 as a therapeutic target in cancer and support the translational development of MBRC-101 as a promising ADC candidate for clinical evaluation, currently in a first-in-human multicenter investigational trial for patients with advanced solid tumors (ClinicalTrials.gov, NCT06014658).

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About MBRC-101

MBRC-101 is an investigational antibody-drug conjugate (ADC) that uniquely targets the EphA5 receptor tyrosine kinase, which is present in multiple cancers including, but not limited to, breast, non-small cell lung (NSCLC), colorectal, gastric, and pancreatic cancers. MBRC-101 is currently being evaluated in the MBRC-101-001 Phase 1/1b clinical trial, a first-in-human, open-label, multicenter, dose escalation and dose expansion study enrolling patients with advanced metastatic solid tumors refractory to standard-of-care treatment. For more information about the MBRC-101-001 clinical trial and to review patient eligibility criteria visit clinicaltrials.gov (NCT06014658).

About MBrace Therapeutics

MBrace is a clinical-stage pharmaceutical company focused on the development and commercialization of novel therapeutic agents for patients with cancer. MBrace develops innovative treatments for cancer patients by developing and validating novel antibody-drug conjugates using the SPARTA technology pioneered by its founders. MBrace is headquartered in San Diego, CA, with research facilities at The Thomas O. Daniel Research Incubator in Summit, NJ. For additional information, please visit MBrace’s website at www.mbracetrx.com.