The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity testing and for predicting adverse outcomes in human patients. Most human therapeutic antibodies trigger xenogeneic responses in wild-type animals and thus rapid clearance of the drugs, which makes in vivo toxicological testing of human antibodies challenging. Here we report the generation of Göttingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains γ1 and γ4 and the immunoglobulin light chain κ. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1κ-isotype monoclonal antibodies daratumumab and bevacizumab, and elicited antibodies against the checkpoint inhibitor atezolizumab and the engineered interleukin cergutuzumab amunaleukin. The humanized minipigs can facilitate the safety and efficacy testing of therapeutic antibodies.

大多数人类重组蛋白的安全性可以在对特定人类蛋白耐受的转基因小鼠中进行评估。然而，由于遗传多样性不足和免疫机制的根本差异，人类疾病的小动物模型通常不适合进行免疫原性测试和预测人类患者的不良结果。大多数人类治疗抗体会在野生型动物中引发异种反应，从而快速清除药物，这使得人类抗体的体内毒理学测试具有挑战性。在这里，我们报告了携带免疫球蛋白重链 γ1 和 γ4 以及免疫球蛋白轻链 κ 人类基因迷你库的哥廷根小型猪的产生。与人类患者的观察结果一致，转基因小型猪能够耐受临床非免疫原性 IgG1κ 同种型单克隆抗体达雷木单抗和贝伐珠单抗，并引发针对检查点抑制剂阿特珠单抗和工程化白介素 cergutuzumab amunaleukin 的抗体。人源化小型猪可以促进治疗性抗体的安全性和有效性测试。