The agonistic potentials of therapeutic anti-CD40 antibodies have been profiled in relation to antibody isotype and epitope specificity. Still, clinical impact relies on a well-balanced clinical efficacy versus target-mediated toxicity. As CD40-mediated immune activation must rely on a combination of stimulation of antigen-presenting cells (APCs) alongside antigen presentation, for efficient T cell priming, alternative approaches to improve the therapeutic outcome of CD40-targeting strategies should focus on providing optimal antigen presentation together with CD40 stimulation. Herein, a bispecific antibody targeting CD40 as a means to deliver cargo (i.e., synthetic peptides) into APCs through a non-covalent, high-affinity interaction between the antibody and the cargo peptide, further referred to as the Adaptable Drug Affinity Conjugate (ADAC) technology, has been developed. The ADAC platform demonstrated a target-specific CD4⁺ and CD8⁺ T cell expansion in vitro and significantly improved peptide-specific CD8⁺ T cell proliferation in vivo. In addition, the strategy dramatically improved the in vitro and in vivo half-life of the synthetic peptides. Future applications of ADAC involve pandemic preparedness to viral genetic drift as well as neoepitope vaccination strategies where the bispecific antibody is an off-the-shelf product, and the peptide antigen is synthesized based on next-generation sequencing data mining.

中文翻译：

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一种适应性强的基于抗体的平台，用于基于激动性 CD40 抗体的灵活合成肽递送

治疗性抗 CD40 抗体的激动潜力与抗体同种型和表位特异性有关。尽管如此，临床影响仍依赖于平衡的临床疗效与靶标介导的毒性。由于 CD40 介导的免疫激活必须依赖于抗原呈递细胞 (APC) 的刺激与抗原呈递的组合，为了有效地启动 T 细胞，改善 CD40 靶向策略治疗结果的替代方法应侧重于提供最佳抗原呈递连同 CD40 刺激。在此，靶向CD40的双特异性抗体作为通过抗体与货物肽之间的非共价、高亲和力相互作用将货物（即合成肽）递送到APC中的手段，进一步称为适应性药物亲和偶联物 (ADAC) 技术，已经开发出来。ADAC 平台展示了一种针对特定目标的 CD4⁺和 CD8 ⁺ T 细胞在体外扩增并显着改善肽特异性 CD8 ⁺ T 细胞在体内的增殖。此外，该策略显着提高了合成肽的体外和体内半衰期。ADAC 的未来应用涉及对病毒遗传漂移的大流行防范以及新表位疫苗接种策略，其中双特异性抗体是现成的产品，肽抗原是基于下一代测序数据挖掘合成的。