Year: 2025
Type: article
Abstract: Introduction: As a crucial asset for human health and modern medicine, an increasing number of biotherapeutics are entering the clinic. However, due to their complexity, these drugs have a higher potential to be immunogenic, leading to the generation of anti-drug antibodies (ADAs). Clinically significant ADAs have an impact on pharmacokinetics (PK), pharmacodynamics (PD), effectiveness, and/or safety. Thus, it is crucial to understand, manage and minimize the immunogenicity potential during drug development, ideally starting from the molecule design stage. Methods: T cell proliferation, to assess the immunogenicity risk of FLT3L-Fc variants. Results: We identified a single point mutation in the human FLT3L-Fc protein that introduced highly immunogenic T cell epitopes, leading to the induction of T cell responses and thereby increasing the immunogenicity risk in clinical settings. Consequently, the variant with this point mutation was removed from further consideration as a clinical candidate. Discussion: This finding underscores the necessity for careful evaluation of mutations during the engineering of protein therapeutics. The integration of multiple immunogenicity risk assessment tools offers critical insights for informed decision-making in candidate sequence design and therapeutic lead selection.
Source: Frontiers in Immunology
Authors: Dan Qin, Qui Phung, Patrick Wu, Zhaojun Yin, Sien Tam, Peter Tran, Adel M. ElSohly, Joshua Gober, Zicheng Hu, Zhenru Zhou, Sivan Cohen, Dongping He, Travis W. Bainbridge, Christopher C. Kemball, Jonathan Zarzar, Alavattam Sreedhara, Nicole Stephens, Jérémie Decalf, Christine Moussion, Zhengmao Ye, Mercedesz Balazs, Yinyin Li
Institution: Genentech
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W4407555245