A first-in-class bifunctional antibody targeting CD20 and CD37 remodels the immune microenvironment in relapsed or refractory B-cell malignancies

BACKGROUND: Bispecific antibodies engaging CD3 have transformed the treatment landscape of B-cell malignancies but remain constrained by T-cell overactivation and cytokine release. Here, we describe PSB202, a first-in-class bifunctional antibody co-targeting CD20 and CD37 to deplete malignant B cells independently of T-cell engagement. METHODS: In this multicenter, open-label phase Ia trial (NCT05003141), adults with relapsed or refractory (R/R) CD20⁺ B-cell non-Hodgkin lymphoma (B-NHL) received escalating doses of PSB202 from 12 to 300 mg. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary endpoints were safety, pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: Fifteen heavily-pretreated patients were enrolled, with a median age of 67.7 years (range, 54-78). One DLT of grade 4 neutropenia occurred at 100 mg. MTD was not reached. PSB202 showed a manageable safety profile, with grade ≥ 3 neutropenia and leukopenia both occurring in 60% of patients. The overall response rate was 30% in 10 evaluable patients, including one complete response at 300 mg. PSB202 achieved sustained B-cell depletion and induced IFN-γ release without cytokine release syndrome. Single-cell sequencing revealed different immune microenvironments in responders and non-responders, and the treatment also induced alterations. CONCLUSIONS: PSB202 may represent a novel dual-targeting strategy that possibly mitigates CD3-related toxicity while promoting cytotoxic immune activation. These findings support further clinical development of PSB202 as an off-the-shelf therapeutic alternative for R/R B-NHL. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov, NCT05003141.