BR105 Is a Novel Anti-Sirpα Monoclonal Antibody That Demonstrates a Favorable Safety Profile and Potent Anti-Tumor Efficacy in Patients with Relapsed/Refractory Lymphoid Malignancies: Preliminary Results from a Phase I Study

Introduction: CD47- SIRPα axis is a prominent innate immune checkpoint signaling pathway that can be harnessed by cancer cells to evade immune surveillance. Mono-antibodies or fusion proteins blocking the interaction of CD47 with SIRPα generate anti-tumor effects in both hematologic malignancies and solid tumors. However, agents targeting CD47 can cause hemolytic anemia due to enrichment of CD47 on healthy red blood cells. BR105 is a novel anti-SIRPα recombinant humanized immunoglobulin G1 monoclonal antibody with silent Fc design that binds to major SIRPα variants to enhance phagocytosis and lacks binding to SIRPγ to avoid T-cell inhibition. In vitro and in vivo data showed favorable safety profiles and anti-tumor effects of BR105 over non-selective SIRPα-targeting antibodies. Here we present the preliminary dose escalation study results from a phase I study of BR105 (NCT05351697) in patients with Relapsed/Refractory (R/R) lymphoid malignancies. Methods: Dose escalation was performed to explore the maximum tolerated dose (MTD) of BR105 monotherapy at 7 dose levels (0.2, 1, 3, 10, 20, 30, 40mg/kg), using a traditional 3+3 design with accelerated titration for the first 2 dose levels. Patients with R/R lymphoid malignancies or advanced solid tumors without standard treatments were enrolled. Results: As of Jun 15th, 2024, dose-escalation part has completed, and a total of 19 patients were enrolled. The pharmacokinetic analysis of BR105 showed dose dependent decrease of clearance. At dose levels of 10 mg/kg and higher, saturation of Target-Mediated Drug Disposition (TMDD) was achieved, and the half-life remained at 8~10 days. PK-PD modeling of clearance versus dose and monocyte receptor occupancy (RO) versus BR105 concentration were performed to characterize RO in whole body as well as RO in peripheral blood, respectively. Results showed that at doses of 10 mg/kg QW or above, peripheral blood RO reached >97% and whole-body RO reached >86%. In 7 patients with lymphoid malignancies (DLBCL[n=2], FL, FDCS, AITL, PTCL, cHL[n=1]), 2 partial responses (ORR 28.6%) were achieved at dose levels with ~ 98% peripheral blood RO (AITL-30mg/kg and cHL-40mg/kg), 5 disease controls (DCR 71.4%) were achieved at dose levels with > 85% peripheral blood RO. Up to 40mg/kg (4 times of the saturated dose), BR105 was well tolerated with no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) has not reached. The frequency of treatment emergent adverse event (TEAE) in patients with lymphoid malignancies were 100%, with 2 (28.57%) ≥Grade 3 (dyspnea, pain), and 1 (14.29%) SAE (pain). The most common TEAEs were interleukin increase in 4 (57.14%), hypokalemia in 3 (42.86%), neutrophil decrease in 3 (42.86%), prothrombin activity increase in 3 (42.86%), leucocyte decrease in 3 (42.86%), anemia in 2 (28.57%), thrombocyte decrease in 2 (28.57%), hyperlipidemia in 2 (28.57%), hyperuricemia in 2 (28.57%), and upper respiratory tract infection in 2 (28.57%) patients. No treatment related adverse events (TRAEs) led to drug discontinuation. No treatment relevant death was reported. One case with upper respiratory tract infection (Grade 2) and one with pain (Grade 3) resulted in delayed drug administration. Conclusions: These results showed that BR105 exhibited satisfactory receptor occupancy in both peripheral blood and whole-body tissues, leading to promising efficacy and safety profiles in lymphoid malignancies. Further investigation as monotherapy or in combination with other agents are ongoing.