No abstract

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in oncology. The use of nanovesicles (NVs) as chemotherapeutic delivery vehicles has been recently proven successful, yet monotherapy with monomodalities remains a significant limitation for solid tumor treatment. Here, as a proof of principle, a novel cell‐membrane‐derived NVs that can display full‐length monoclonal antibodies (mAbs) is engineered. The high affinity and specificity of mAb for tumor‐specific antigens allow these vesicular antibodies (VAs) to selectively deliver a cytotoxic agent to tumor cells and exert potent inhibition effects. These VAs can also regulate the tumor immune microenvironment. They can mediate antibody‐dependent cellular cytotoxicity to eradicate tumor cells via recruitment and activation of natural killer cells in the tumor. Upon further encapsulation with chemotherapeutic agents, the VAs show unequaled cooperative effects in chemotherapy and immunotherapy in tumor‐bearing mice. As far as it is known, this is the first report of a VA‐based multifunctional combination therapy platform. This might lead to additional applications of vesicular antibodies in cancer theranostics.

Background We have previously obtained a mouse anti-hepatitis B surface antigen (HBsAg) antibody E6F6 with long-lasting serum HBsAg clearance effects. The E6F6 epitope-based protein CR-T3-SEQ13 (HBsAg aa 113–135) vaccination therapy in cynomolgus monkeys induced long-term polyclonal antibodies-mediated clearance of HBsAg in the HBV transgenic (HBV-Tg) mice. Methods We isolated monoclonal antibodies from CR-T3-SEQ13 vaccinated cynomolgus monkeys, compared their therapeutic effects with E6F6, identified their epitopes on HBsAg, determined the pharmacokinetics, and studied their physical property. Results A panel of anti-HBsAg mAbs was generated through memory B cell stimulatory culture. Two lead monkey-human chimeric antibodies, C1–23 and C3–23, effectively suppressed HBsAg and HBV DNA in HBV-Tg mice. The humanized antibodies and humanized-mouse reverse chimeric antibodies of two antibodies exhibited comparable HBsAg clearance and viral suppression efficacy as those versions of E6F6 in HBV-Tg mice. Humanized antibody hu1–23 exhibited more efficacy HBsAg-suppressing effects than huE6F6–1 and hu3–23 in HBV-Tg mice at dose levels of 10 mg/kg and 20 mg/kg. Evaluation of the binding sites indicates that the epitope recognized by hu1–23 is located in HBsAg aa 118–125 and 121–125 for hu3–23. Physical property study revealed that hu1–23 and hu3–23 are stable enough for further development as a drug candidate. Conclusions Our data suggest that the CR-T3-SEQ13 protein is a promising HBV therapeutic vaccine candidate; and hu1–23 and hu3–23 are therapeutic candidates for the treatment of CHB. Moreover, the generation of antibodies from the epitope-based vaccinated subjects may be an alternative approach for novel antibody drug discovery. Statement of Significance Cynomolgus monkey mAbs were generated from an HBsAg-epitope-based-protein vaccination through memory B cell stimulatory culture. The humanized antibodies can efficiently mediate HBsAg clearance in HBV-Tg mice and may serve as anti-HBsAg therapeutic candidates. Generation of mAbs from the epitope-based vaccinated subjects is an alternative approach for novel antibody discovery.