First-generation and preclinical evaluation of an EphA5-targeted antibody-drug conjugate in solid tumors
Fernanda I Staquicini1, Fenny Hf Tang2,3, Vanessa de Oliveira1
1MBrace Therapeutics, San Diego, California, USA.
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 a ThioBridge, thereby ensuring 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).
Insights
MBRC-101, a novel antibody-drug conjugate targeting EphA5, demonstrates potent antitumor activity in preclinical models. This targeted therapy shows promise for treating various solid tumors with limited toxicity, advancing to clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cancer treatment is evolving towards targeted therapies for improved outcomes.
- EphA5, a receptor tyrosine kinase, has roles in development but is understudied in cancer.
- Antibody-drug conjugates (ADCs) offer targeted delivery of cytotoxic agents.
Purpose of the Study:
- To design and evaluate MBRC-101, a novel ADC targeting EphA5.
- To assess EphA5 expression in various solid tumors and normal tissues.
- To determine the preclinical efficacy and safety of MBRC-101.
Main Methods:
- MBRC-101 developed as an anti-EphA5 antibody conjugated to monomethyl auristatin E (MMAE) via ThioBridge.
- EphA5 expression analyzed in diverse solid tumor types and normal tissues.
- Antitumor activity evaluated in patient-derived xenograft models.
- Preclinical toxicology studies conducted in rats and nonhuman primates under Good Laboratory Practice (GLP) conditions.
Main Results:
- EphA5 is significantly expressed in multiple solid tumors (aerodigestive, genitourinary, breast) but minimally in normal tissues.
- MBRC-101 demonstrated potent antitumor activity, achieving complete tumor regression in xenograft models.
- GLP toxicology studies showed MBRC-101 was well tolerated, with toxicities consistent with MMAE exposure.
Conclusions:
- EphA5 is validated as a promising therapeutic target for cancer.
- MBRC-101 exhibits favorable preclinical efficacy and safety profiles.
- MBRC-101 is a promising ADC candidate advancing to first-in-human clinical trials for advanced solid tumors.
