Background
CD40 is a molecule required for activation of antigen-presenting cells (APCs). Agonistic antibodies against CD40 showed promising results in clinical trials for various cancers, however their administration is associated with various adverse events including cytokine release syndrome and hepatotoxicity. One of the approaches to decrease toxicity of agonistic anti-CD40 antibodies is to utilize bispecific antibodies (BsAb) which also bind molecules abundant in the tumor and not in other tissues. Considering favorable outcomes shown by checkpoint inhibitors in the clinic, PD1 and PDL1 are used as the second target in agonistic anti-CD40 BsAbs.
Methods
We have developed a physiologically based pharmacokinetic (PBPK) model describing distribution of PD1xCD40 and PDL1xCD40 BsAbs between compartments (blood, tumor, lymph nodes, other tissues) and their binding to targets (CD40 on APCs and tumor cells, PD1 on T cells, PDL1 on APC, tumor cells, and T cells). In the model, endothelial cells are considered the primary site of antibody degradation. The antibodies are also eliminated through binding with their targets and internalization (target-mediated drug disposition, TMDD). Formation of a trimeric complex (either PD1:BsAb:CD40 or PDL1:BsAb:CD40) occurs in an immunological synapse between the corresponding cells. For PD1xCD40 BsAb kinetic parameters, YH008 antibody was used;1 for PDL1xCD40 BsAb, HBM9027 antibody.2
Results
The model was validated using PK data for monospecific antibodies against PD1 (pembrolizumab, nivolumab), PDL1 (avelumab, durvalumab, atezolizumab), and CD40 (selicrelumab, Chi Lob 7/4, BI 655064), and showed good agreement with clinical data. Comparison of PD1xCD40 and PDL1xCD40 BsAbs using the model showed that maximum concentration of the trimeric complexes is achieved at doses 50 and 275 mg, respectively. While disruption of PD1:PDL1 complexes is lower for PDL1xCD40 BsAb than for PD1xCD40, they show similar levels of CD40 engagement, however, higher doses of PDL1xCD40 BsAb are required.
Conclusions
The developed PBPK model integrating data on immune cell levels, target expression, and binding parameters of PD1xCD40 and PDL1xCD40 BsAbs predicts PK and receptor occupancy of the antibodies in tumor and plasma. The model shows that higher doses of PDL1xCD40 BsAb are required for maximal engagement of target molecules compared to PD1xCD40 BsAb.
References
Baihong L, et al. A novel PD1-CD40 bispecific antibody YH008 induces potent anti-tumor activity in-vivo by PD1 dependent activation of CD40 signaling. Cancer Res. 2021;81(13_Supplement):1852.
Luo H, et al. Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy. Cancer Res. 2022;82(12_Supplement):5559.