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Publication Abstract from PubMed

Bispecific antibodies (Bispecifics) demonstrate exceptional clinical potential to address some of the most complex diseases. However, Bispecific production in a single cell often requires the correct pairing of multiple polypeptide chains for desired assembly. This is a considerable hurdle that hinders the development of many immunoglobulin G (IgG)-like bispecific formats. Our approach focuses on the rational engineering of charged residues to facilitate the chain pairing of distinct heavy chains (HC). Here, we deploy structure-guided protein design to engineer charge pair mutations (CPMs) placed in the CH3-CH3' interface of the fragment crystallizable (Fc) region of an antibody (Ab) to correctly steer heavy chain pairing. When used in combination with our stable effector functionless 2 (SEFL2.2) technology, we observed high pairing efficiency without significant losses in expression yields. Furthermore, we investigate the relationship between CPMs and the sequence diversity in the parental antibodies, proposing a rational strategy to deploy these engineering technologies.

Next generation Fc scaffold for multispecific antibodies.,Estes B, Sudom A, Gong D, Whittington DA, Li V, Mohr C, Li D, Riley TP, Shi SD, Zhang J, Garces F, Wang Z iScience. 2021 Nov 15;24(12):103447. doi: 10.1016/j.isci.2021.103447. eCollection , 2021 Dec 17. PMID:34877503^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.