Pharmacokinetics, pharmacodynamics, and biomarkers of lbl-034, a GPRC5D-targeted T cell engager, in a first-in-human phase Ⅰ/Ⅱ study in relapsed/refractory multiple myeloma

Abstract

Abstract Introduction: LBL-034 is a humanized IgG1 subtype asymmetric bispecific antibody targeting GPRC5D and CD3 with a 2:1 format. Its affinity-optimized anti-CD3 arm, engineered with steric hindrance, enables conditional T cell activation and proliferation. Preliminary findings were presented at ASH 2024 (Abstract 4736). The objective of this analysis is to further evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and biomarker profiles of LBL-034, explore their correlation with clinical responses in the ongoing clinical study (NCT06049290). Methods This ongoing phase Ⅰ/Ⅱ, open-label study consists of a dose escalation stage followed by dose expansion. LBL-034 was administered intravenously at escalating dose levels of 10, 30, 80, 200, 400, 800 and 1200 μg/kg on Days 1 and 15 of each 4-week cycle (Q4W). To mitigate the risk of cytokine release syndrome (CRS), priming doses were applied across 80-1200 μg/kg cohorts. Bone marrow and peripheral blood samples were collected at multiple time points for the evaluation of PK/PD/biomarkers. The sample detection methods were as follows:Serum PK were assessed using a validated ELISA method, and PK parameters were calculated by Phoenix WinNonlin (8.4).Two validated multicolor flow cytometry (FC) panels were used to detect serum T cell subtypes and activation related markers: panel one (CD45, CD3, CD4, CD8), panel two (CD45, CD3, CD4, CD8, CD25, Ki67, PD1, Tim3).Bone marrow CD138+CD19- plasma cell subtypes, percentages, and absolute counts were evaluated using an 8-color FC (CD138, CD38, CD45, CD19, GPRC5D, CD56, CD117, BCMA).Serum cytokines (TNF-α, IFN-γ, IL-6) and soluble BCMA (sBCMA) were measured using validated commercial kits. Minimal residual disease (MRD) negativity in bone marrow aspirates was evaluated by next-generation sequencing (Seq-MRD®). Results As of July 15, 2025, PK profiles of LBL-034 were available for 56 patients, 38 of whom completed intensive blood sampling: 10 μg/kg (n=1), 30 μg/kg (n=1), 80 μg/kg (n=5), 200 μg/kg (n=5), 400 μg/kg (n=12), 800 μg/kg (n=7), and 1200 μg/kg (n=7). Preliminary PK results suggested that LBL-034 exposure increased as dose increased, and T1/2 reached up to 9.4 days in Cycle 1. Steady state concentrations were attained by Cycle 3, with an estimated T1/2 of approximately 23 days, supporting the feasibility of Q2W, Q3W, or potentially Q4W dosing schedules. LBL-034 induced rapid depletion of GPRC5D+CD138+CD19- plasma cells, with a 98.97% reduction of absolute cell counts observed by Cycle 2 Day 1 (C2D1) in responders. This was accompanied by consistent reductions in serum sBCMA levels, with maximal declines exceeding 95% in patients achieving complete response (CR) or stringent complete response (sCR). The magnitude of sBCMA reduction correlated closely with the depth of response. Among patients with ≥CR and evaluable MRD data (n=19), MRD negativity rates were 84.2% and 68.4% at the 10⁻⁵ and 10⁻⁶ thresholds, respectively, the earliest conversion to MRD-negative status occurred at C2D1. In the intent-to-treat (ITT) population (n=56), the MRD negativity rate at 10⁻⁵ for LBL-034 was approximately 20% higher than the historical rate reported for talquetamab (Rasche et al., ASCO 2025, Abstract 7528). T cell redistribution, characterized by a transient decrease in peripheral CD3+ T cells, was observed following the first priming dose, with recovery by C2D1, consistent with the mechanism of action of LBL-034. Robust T cell activation was observed in responders, demonstrated by increased CD8+ T cells co-expressing CD25+, Ki67+, PD1+, and Tim3+ during Cycle 1. Notably, reduced cytokine release was observed during the priming dose phase, which could be attributed to the unique molecular format of LBL-034, and contributed to a lower CRS risk at efficacious dose levels starting from 80 μg/kg. Conclusions LBL-034 exhibited an excellent PK profile, characterized by a prolonged half-life that supports Q3W or Q4W dosing schedules. Its proposed mechanism of action, initially validated in a humanized MM xenograft mouse model, was further confirmed in clinical settings by peripheral T cell redistribution and minimal cytokines release. Reduction in bone marrow GPRC5D+CD138+CD19- plasma cells and serum sBCMA levels correlated strongly with clinical responses and MRD status.