Abstract
Interleukin 17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells. Antibody BCD-085 (netakimab) against human IL-17A is one of the new inhibitors of this cytokine. In netakimab, the VH domain is replaced by the VHH domain of Lama glama possessing a long complementarity determining region (CDR-H3) in its heavy chain. Here we demonstrate the high affinity of IL-17A to the Fab fragment of netakimab and to its integral part, the VHH domain. We have determined the crystal structure of the Fab fragment of netakimab at 1.9 Å resolution. High variability in the orientation of light and heavy chains of the Fab fragment of netakimab was shown, which is determined by the peculiarity of the structural organization of the CDR-H3. As the high conformational plasticity of the molecule hampers modeling the Fab fragment of netakimab complexed to IL-17A, we have carried out modeling the complex between the antigen and the integral part of the Fab fragment, the VHH domain. We explain the high netakimab Fab fragment affinity for IL-17A by a large number of protein–protein contacts due to additional interactions between CDR-H3 and the cytokine dimer.
Highlights
Cytokine Interleukin 17A (IL-17A) plays a key role in protecting an organism against extracellular bacterial and fungal infections [1]
We present the crystal structure of the netakimab Fab fragment, which is directed against the IL-17A, kinetic analysis of the interaction between IL-17A with the Fab fragment and its integral part, the VH H domain, and modeling the interactions in the IL-17A/VH H domain complex
We suggested that tighter contact between the VH H domain of the netakimab Fab fragment and the IL-17A region that interact with the IL-17 RA receptor provides high functional activity of the preparation
Summary
Cytokine IL-17A plays a key role in protecting an organism against extracellular bacterial and fungal infections [1]. Substantial progress has been achieved in the therapy of such diseases, which was associated with the widespread introduction of therapeutic preparations based on anti-IL-17 antibodies [3]. Preparations based on non-canonical immunoglobulins (HCAb) are being extensively developed. These antibodies do not contain the light chain. HCAbs were first discovered in dromedary [4]. Later it was shown that HCAbs, as well as classical antibodies, are present in the blood of cartilaginous fish and mammals of the Camelidae family. HCAbs were found in the blood of humans exposed to gamma radiation, though, in this case, they were non-functional
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