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83 Translational PBPK modeling of PET imaging reveals enhanced predicted tumor exposure of antiCTLA4 singledomain antibody fragments vs. monoclonal antibodies

Year: 2026

Type: conference-abstract

Abstract: Background Limited tumor penetration is a key challenge for monoclonal antibody (MAb) therapeutics due to their large molecular size. Single-domain antibody fragments (VHHs) are substantially smaller and may demonstrate improved tumor penetration and accumulation. To evaluate this potential advantage, anti-CTLA-4 MAbs and VHHs were assessed using positron emission tomography (PET) imaging and physiologically based pharmacokinetic (PBPK) modeling to enable translation to human cancer patients.Methods All evaluated molecules were conjugated to p-SCN-Bn-Deferoxamine (DFO) and radiolabeled with 89Zr (half-life = 3.3 d). In mice, an anti-mouse CTLA-4 MAb (9D9-IgG2a) and a corresponding VHH were evaluated in the CT26 tumor model. In non-human primates (NHPs), an anti-human CTLA-4 MAb (ipilimumab), an anti-human CTLA-4 VHH, and control agents (anti-RSV MAb and VHH) were assessed in healthy rhesus monkeys. PET imaging was performed for up to 9 days post-administration to quantify tumor uptake, biodistribution, and clearance. PBPK models were developed using PET-derived tissue and blood data to predict human tumor exposure.Results In mice, the VHH demonstrated higher initial tumor uptake compared with the MAb (21.9 ± 5.6 vs. 19.3 ± 1.5 %ID/g), but exhibited reduced retention over 7 days, consistent with faster systemic clearance. In NHPs, overall biodistribution and pharmacokinetics were comparable across agents. However, lymph node uptake of the anti-CTLA-4 VHH was markedly higher than that of the control VHH (7.2 ± 2.2 vs. 2.2 ± 0.4 SUV_max) and both MAbs (2.1 ± 0.4 and 2.2 ± 0.2 SUV_max). K D obtained by surface plasmon resonance analysis indicated stronger binding affinity of the VHH to rhesus CTLA-4 compared with the MAb (0.07 nM vs. 1.8 nM). Translational PBPK modeling based on PET data predicted an approximately 1.5-fold increase in tumor exposure for the VHH relative to the MAb at equivalent systemic exposure in humans.Conclusions PET imaging combined with PBPK modeling enabled quantitative comparison of tumor exposure and tissue distribution of anti-CTLA-4 formats. The enhanced lymph node uptake of the VHH in NHPs suggests target-mediated accumulation driven by higher CTLA-4 binding affinity. In contrast, the MAb showed limited evidence of comparable target engagement, potentially reflecting differences in tissue accessibility or affinity. Translational PBPK modeling predicts that VHHs may achieve modestly improved tumor exposure relative to conventional MAbs in humans, supporting their continued evaluation as an alternative therapeutic modality.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0083