First-generation and preclinical evaluation of an EphA5-targeted antibody-drug conjugate in solid tumors
Fernanda I. Staquicini, Fenny H.F. Tang, Vanessa de Oliveira, Sun-Young Kim, Ethan R. Chen, Christopher Markosian, Daniela I. Staquicini, Yongjian Wu, J. Kellogg Parsons, Kirstin F. Barnhart, Stephen C. Alley, Isan Chen, Wadih Arap, Renata Pasqualini
Fernanda I. Staquicini, Fenny H.F. Tang, Vanessa de Oliveira, Sun-Young Kim, Ethan R. Chen, Christopher Markosian, Daniela I. Staquicini, Yongjian Wu, J. Kellogg Parsons, Kirstin F. Barnhart, Stephen C. Alley, Isan Chen, Wadih Arap, Renata Pasqualini
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Research Article Oncology

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 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).

Authors

Fernanda I. Staquicini, Fenny H.F. Tang, Vanessa de Oliveira, Sun-Young Kim, Ethan R. Chen, Christopher Markosian, Daniela I. Staquicini, Yongjian Wu, J. Kellogg Parsons, Kirstin F. Barnhart, Stephen C. Alley, Isan Chen, Wadih Arap, Renata Pasqualini

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Figure 4

MBRC-101 antitumor activity.

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MBRC-101 antitumor activity. (A) IHC of tissue sections from a PDX model...
(A) IHC of tissue sections from a PDX model of TNBC shows moderate and heterogenous expression of EphA5. Scale bar, 200 μm. Weight of tumors collected at the end of the dose-range-finding study confirmed antitumor activity of MBRC-101 at clinically relevant dose levels. Data are presented as means ± SEM. Statistical tests were ordinary 1-way ANOVA coupled with post hoc Tukey’s multiple comparisons test. (B) Histological analysis of tissue sections of tumors collected at the end of treatment. The pan-tumor marker PAN-CK was used to detect cancer cells, and Ki-67 served to detect proliferating cancer cells (arrows). The Ki-67 proliferation index was assessed by point counting from 500 to 1,000 cells and reported as percent positive cells. Scale bar, 20 μm. (C) MBRC-101 antitumor activity compared with sacituzumab govitecan, an FDA-approved ADC for the treatment of TNBC. Data are presented as means ± SEM. Statistical tests were 2-way ANOVA coupled with post hoc Tukey’s multiple comparisons test among treatment groups.