Deciphering the Efficacy and Safety of TRPH-222: A New Horizon in Anti-CD22 ADC Therapy for NHL

CD22, a glycoprotein specific to B cells, is frequently overexpressed in B-cell malignancies such as NHL, DLBCL, MCL, and various leukemias. Its limited expression and quick internalization upon antibody binding make it a promising target for ADC therapies. However, past attempts to create CD22-targeting ADCs have faced clinical limitations due to a poor therapeutic index.

TRPH-222 is a novel ADC that features an anti-CD22 antibody with a site-specific modification to incorporate formylglycine, enabling the attachment of a maytansinoid payload through a SMARTAG conjugation method. This approach ensures a maximum drug-to-antibody ratio (DAR) of 2.0, potentially enhancing the therapeutic window.

In a WSU-DLCL2 xenograft model, TRPH-222 administered intravenously at varying doses once a week significantly reduced tumor volume, outperforming rituximab. In SU-DHL-2 and Granta-519 xenografts, the drug maintained tumor stasis at a weekly dose of 10mg/kg.

The tolerability and pharmacokinetics of TRPH-222 were assessed in cynomolgus monkeys with doses given every three weeks. The drug was well tolerated without any treatment-related effects on clinical observations or body weight. Minor increases in AST and ALT activities were observed at higher doses, alongside microscopic liver changes that were not considered adverse.

Preliminary pharmacokinetic data indicated the stability and long half-life of TRPH-222, suggesting that the linker is stable in vivo. The study concludes that TRPH-222 exhibits considerable anti-tumor activity across several B-cell lymphoma models and is well tolerated at high doses in monkeys. IND-enabling safety studies are underway, with the aim of advancing TRPH-222 for clinical evaluation.

The findings indicate that TRPH-222 may offer a substantial therapeutic window due to the stable conjugation of the maytansinoid payload. The doses tolerated in monkeys correspond to human equivalent doses that are significantly higher than most ADCs, positioning TRPH-222 as a potential best-in-class therapy for NHL and a leading ADC technology.