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Background Rilvegostomig is a monovalent, bispecific humanized IgG1 monoclonal antibody with high-affinity binding to both human PD-1 and TIGIT. This dual-targeting approach has demonstrated notable antitumor activity and a favorable safety profile in adult patients with non-small cell lung cancer (NSCLC) in a Phase I/II clinical trial ( NCT04995523).1 Rilvegostomig is currently progressing through multiple Phase II and III clinical trials.Our work characterizes rilvegostomig’s binding to T cells expressing varying levels of PD-1 and TIGIT. We hypothesized that it achieves superior PD-1 saturation on PD-1/TIGIT dual-positive cells at lower concentrations due to its bispecific format and preferential TIGIT binding. Furthermore, we contrasted rilvegostomig’s preferential binding to PD-1/TIGIT dual-expressing tumor infiltrating lymphocytes (TILs), which constitute ~40% of TILs within patient-resected NSCLC tumors, against co-formulations of bivalent PD-1 + αTIGIT antibodies and clinically approved PD-1 antibodies.Methods To assess receptor occupancy (RO), we treated human CD8 T cells, highly expressing PD-1 and TIGIT, with titrations of PD-1/TIGIT-targeting agents. We then measured detectable PD-1 and TIGIT receptors using flow cytometry with competing fluorescently labeled antibodies. Similarly, we administered titrations of these agents to dissociated tumor tissues from resected NSCLC patient samples. We quantified available PD-1 and TIGIT receptor densities on CD8 T cells, CD4 T cells, regulatory T cells (Tregs), and NK cells via flow cytometry to assess drug distribution as a function of receptor density.Results Rilvegostomig demonstrates a significantly stronger affinity for TIGIT (K D =15 pM) than for PD-1 (KD =320 pM) (Lee et al., SITC 2022). This enables full TIGIT RO at lower concentrations compared to a traditional αPD-1 mAb, effectively ‘anchoring’ rilvegostomig to target cells via its anti-TIGIT arm. Rilvegostomig’s bispecific format profoundly enhances the binding kinetics of its PD-1 arm in the context of PD-1/TIGIT dual-expressing cells—a phenomenon called ‘cooperative binding.’ As a result, rilvegostomig achieves PD-1 saturation at a lower concentration compared to both monovalent and bivalent anti-PD-1 antibodies on dual-expressing cells. Furthermore, rilvegostomig exhibits strong preferential binding to TIGIT-expressing cells, even in mixed populations.Conclusions Rilvegostomig’s potent, preferential TIGIT binding and cooperative PD-1 engagement led to superior receptor saturation of PD-1/TIGIT dual-positive cells at lower concentrations than conventional anti-PD-1 antibodies. This enhanced, selective targeting of TIGIT-expressing cells and simultaneous blockade of both TIGIT and PD-1 on dual-expressing TILs suggests a significant advantage over conventional anti-PD-(L)1 therapeutic strategies. These mechanistic insights support rilvegostomig’s observed clinical activity in NSCLC and validate its differentiated mechanism due to its monovalent bispecific format.Reference Hiltermann TJN, Izumi H, Cho BC, Cunha S, Danchaivijitr P, Felip E, Ho GF, Leventakos K, Li Y, Sugawara S, Voon PJ, Wauters E, Yang TY, Brandão M, Chen H, Achour I, Colebrook S, Sone K, Bhulani N, Karanovic D, Wang Y. Efficacy and safety of rilvegostomig, an anti-PD-1/ TIGIT bispecific, for CPI-naïve metastatic NSCLC with PD-L1 1-49% or ≥50%. J Thorac Oncol. 2024;19:10,S33.