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China's D3 Bio advances TIGIT/PVRIG bispecific D3L-002 into first-in-human testing

Edited by Robert McTiernan··2 min read
China's D3 Bio advances TIGIT/PVRIG bispecific D3L-002 into first-in-human testing

China-based D3 Bio (Wuxi) Co., Ltd has registered a first-in-human trial of D3L-002, an internally discovered bispecific antibody designed to simultaneously block two inhibitory immune checkpoints — TIGIT and PVRIG — in patients with advanced solid tumors. The trial arrives as the TIGIT field is reassessing its clinical assumptions following high-profile monospecific failures, and the dual-targeting approach reflects a broader hypothesis that blocking the PVRIG arm of the same ligand axis may be necessary to achieve meaningful immune reactivation.

The Phase I dose-escalation study (NCT07667842) will enroll approximately 24 adults with histologically confirmed metastatic or locally advanced solid tumors that have progressed on at least one prior line of therapy. D3L-002 is administered intravenously every three weeks in 21-day cycles, with dose escalation guided by a Bayesian Optimal Interval (BOIN) design across four planned cohorts. The trial, expected to begin in July 2026 with primary data anticipated by November 2027, excludes patients with prior anti-TIGIT or anti-PVRIG therapy — a criterion that both defines the intended treatment-naive checkpoint population and signals the company's intent to position D3L-002 ahead of, rather than after, existing checkpoint agents. Preliminary antitumor activity, assessed by objective response rate and disease control rate per RECIST v1.1, is a secondary endpoint.

TIGIT and PVRIG are co-expressed inhibitory receptors on activated T cells and natural killer cells, and both compete with the activating receptor DNAM-1 (CD226) for access to shared tumor-expressed ligands — CD155 (PVR) and CD112 (PVRL2/Nectin-2), respectively. Because CD112 binds PVRIG with higher affinity than it binds TIGIT, blocking TIGIT alone leaves a significant inhibitory signal intact through the PVRIG-CD112 interaction. D3L-002 is designed to block both interactions simultaneously, with preclinical data presented at SITC 2023 showing restored T and NK cell function and anti-tumor activity in vitro — though the specific bispecific format and any Fc-mediated effector functions have not been publicly disclosed.

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The approach enters the clinic after several late-stage disappointments for monospecific anti-TIGIT antibodies, prompting renewed interest in combination checkpoint strategies targeting the broader DNAM-1 axis. Clinical development of TIGIT/PVRIG bispecific antibodies remains at an early stage but is becoming increasingly competitive. Jiangsu Hengrui's SHR-2002 was among the earliest programs to enter Phase I clinical testing in 2021, followed by Biotheus' PM1009 and Simcere Zaiming's SIM0348. Early efforts to co-target the DNAM-1 checkpoint axis have also included Compugen's combination strategy pairing the anti-PVRIG antibody COM701 with the anti-TIGIT antibody COM902 rather than integrating both specificities into a single molecule. D3L-002 therefore joins a small but expanding class of TIGIT/PVRIG bispecific antibodies, where differentiation is likely to depend on antibody engineering, safety, pharmacokinetics, and clinical activity rather than target selection alone.

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