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Flisikowska, Tatiana; Egli, Jerome; Flisikowski, Krzysztof; Stumbaum, Marlene; Kueng, Erich; Ebeling, Martin; Schmucki, Roland; Georges, Guy; Singer, Thomas; Kurome, Mayuko; Kessler, Barbara; Zakhartchenko, Valeri; Wolf, Eckhard; Weber, Felix; Schnieke, Angelika and Iglesias, Antonio (2022): A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies. In: Nature Biomedical Engineering, Vol. 6, No. 11: pp. 1248-1256

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Abstract

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 Gottingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains gamma 1 and gamma 4 and the immunoglobulin light chain kappa. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1K-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.

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