TUB-010, a Novel Anti-CD30 Antibody–Drug Conjugate Based on Tub-Tag Technology, Widens the Therapeutic Window by Reducing Toxicity While Maintaining High Efficacy

TUB-010 is a next-generation antibody-drug conjugate (ADC) targeting CD30 expressed on various hematopoietic malignancies such as Hodgkin lymphoma. Among the therapeutic options for patients with relapsed and refractory CD30-positive cancers is brentuximab vedotin (Adcetris), a monomethyl auristatin E (MMAE)-delivering anti-CD30 ADC with a mean drug-to-antibody ratio of 4. Adcetris exhibits a high response rate at the cost of significant toxicities, likely driven by the payload MMAE and the instability of the maleimide conjugation chemistry. TUB-010 uses the same antibody and payload as Adcetris but is based on the Tub-tag conjugation strategy, which stably attaches MMAE to the hydrophilic Tub-tag peptides on the light chains via chemoenzymatic conjugation. This new technology enables the generation of a homogeneous and site-specific drug-to-antibody ratio 2 ADC with unique biophysical properties. TUB-010 demonstrates similar binding and lysosomal release characteristics as Adcetris, which translates into comparable in vitro cytotoxicity on CD30-positive cell lines when normalized to the MMAE concentration. Importantly, TUB-010 exhibits higher stability with negligible premature deconjugation in circulation and reduced aggregation, as well as lower nonspecific cytotoxicity on target-negative cells compared with Adcetris. As a consequence, TUB-010 induces superior tumor control compared with Adcetris when dosed at equal MMAE concentrations in vivo and also lower toxicity and higher tolerability in rodents and nonhuman primates. Taken together, TUB-010 is a novel, potential best-in-class anti-CD30 ADC with improved biophysical properties designed to deliver MMAE with higher precision and a wider therapeutic window than Adcetris using Tub-tag technology. Therefore, TUB-010 may increase the clinical benefit of anti-CD30 ADC therapies.