3wn5
Crystal structure of asymmetrically engineered Fc variant in complex with FcgRIIIa
Structural highlights
DiseaseIGHG1_HUMAN Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4. FunctionPublication Abstract from PubMedEnhancing the effector function by optimizing the interaction between Fc and Fcgamma receptor (FcgammaR) is a promising approach to enhance the potency of anticancer monoclonal antibodies (mAbs). To date, a variety of Fc engineering approaches to modulate the interaction have been reported, such as afucosylation in the heavy chain Fc region or symmetrically introducing amino acid substitutions into the region, and there is still room to improve FcgammaR binding and thermal stability of the CH2 domain with these approaches. Recently, we have reported that asymmetric Fc engineering, which introduces different substitutions into each Fc region of heavy chain, can further improve the FcgammaR binding while maintaining the thermal stability of the CH2 domain by fine-tuning the asymmetric interface between the Fc domain and FcgammaR. However, the structural mechanism by which the asymmetrically engineered Fc improved FcgammaR binding remained unclear. In order to elucidate the mechanism, we solved the crystal structure of a novel asymmetrically engineered Fc, asym-mAb23, in complex with FcgammaRIIIa. Asym-mAb23 has enhanced binding affinity for both FcgammaRIIIa and FcgammaRIIa at the highest level of previously reported Fc variants. The structural analysis reveals the features of the asymmetrically engineered Fc in comparison with symmetric Fc and how each asymmetrically introduced substitution contributes to the improved interaction between asym-mAb23 and FcgammaRIIIa. This crystal structure could be utilized to enable us to design a more potent asymmetric Fc. Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for FcgammaRs.,Mimoto F, Kadono S, Katada H, Igawa T, Kamikawa T, Hattori K Mol Immunol. 2014 Mar;58(1):132-8. doi: 10.1016/j.molimm.2013.11.017. Epub 2013, Dec 14. PMID:24334029[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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