Abstract：
:Reduction of the affinity of the fragment crystallizable (Fc) region with immune receptors by substitution of one or a few amino acids, known as Fc-silencing, is an established approach to reduce the immune effector functions of monoclonal antibody therapeutics. This approach to Fc-silencing, however, is problematic as it can lead to instability and immunogenicity of the developed antibodies. We evaluated loop grafting as a novel approach to Fc-silencing in which the Fc loops responsible for immune receptor binding were replaced by loops of up to 20 amino acids from similar local environments in other human and mouse antibodies. Molecular dynamics simulations of the designed variants of an Fc region in a complex with the immune receptor FcγIIIa confirmed that loop grafting potentially leads to a significant reduction in the binding of the antibody variants to the receptor, while retaining their stability. In comparison, standard variants with less than eight substituted amino acids showed possible instability and a lower degree of Fc-silencing due to the occurrence of compensatory interactions. The presented approach to Fc-silencing is general and could be used to modulate undesirable side effects of other antibody therapeutics without affecting their stability or increasing their immunogenicity.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Lešnik S,Hodošček M,Podobnik B,Konc Jdoi
10.1021/acs.jcim.9b01198subject
Has Abstractpub_date
2020-11-23 00:00:00pages
5475-5486issue
11eissn
1549-9596issn
1549-960Xjournal_volume
60pub_type
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