Engineered Anti-CD40 Agonist Antibody for Cancer Vaccine Delivery

Cancer vaccines targeting patient-derived neoantigens offer great promise for personalized cancer therapy but face challenges in achieving targeted delivery to antigen-presenting cells (APCs) to elicit robust and durable cancer-specific immune responses. We synthesized an anti-mouse CD40 agonistic–monovalent streptavidin fusion antibody (αCD40-mSAs), which enables targeted delivery of biotinylated neoantigen peptides to APCs in draining lymph nodes (dLNs). αCD40-mSAs were validated for mSA expression and demonstrated strong binding affinities to mouse CD40 and biotin. Advanced imaging demonstrated that αCD40-mSAs enhances homing to dLNs and intracellular delivery of neoantigen peptides to critical APC subsets, such as cDC1. The potent agonistic effects of αCD40-mSAs on dendritic cell maturation, activation, and antigen presentation were verified through in vitro assays. Vaccination with αCD40-mSAs elicited robust cancer-specific CD8⁺ T cell responses, leading to significant tumor regression and prevention in a mouse tumor model. These results support αCD40-mSAs as an 'all-in-one' vaccine delivery platform with multifunctional immunopharmacological advantages and strong translational potential for personalized cancer vaccination.