Enhanced safety and efficacy profile of CD40 antibody upon encapsulation in pHe-triggered membrane-adhesive nanoliposomes.

Aim: To develop pH (pHe)-triggered membrane adhesive nanoliposome (pHTANL) of CD40a to enhance anti-tumor activity in pancreatic cancer while reducing systemic toxicity.

Materials And Methods: A small library of nanoliposomes (NL) with various lipid compositions were synthesized to prepare pH (pHe)-triggered membrane adhesive nanoliposome (pHTANL). Physical and functional characterization of pHTANL-CD40a was performed via dynamic light scattering (DLS), Transmission Electron Microscopy (TEM), confocal microscopy, and flow cytometry. In vivo studies were performed using PDAC (Panc02) transplanted mice. Tumor tissue was analyzed by flow cytometry, and plasma cytokines and liver enzymes were analyzed by ELISA.

Results: pHTANL-CD40a reduced tumor growth, enhanced tumor immune infiltration/activation, and enhanced survival compared to vehicle and free-CD40a. Importantly, pHTANL-CD40a treatment resulted in significantly lower systemic toxicity as indicated by unchanged body weight, minimal organ deformity, and reduced serum levels of liver enzyme alanine transaminase (ALT) and inflammatory cytokine IL-6.

Conclusion: pHTANL-CD40a is more effective than free CD40a in anti-tumor activity, especially in altering the TME immune landscape for a potential therapeutic benefit in combination with immunotherapy.