Enhancing CDC and ADCC of CD19 Antibodies by Combining Fc Protein-Engineering with Fc Glyco-Engineering

Antibodies

IraAlexandra Münnich¹  Christian Kellner¹  Andreas Humpe¹  Sebastian Lutz¹  Katja Klausz²  Thomas Valerius²  Thies Rösner²  Martin Gramatzki²  Matthias Peipp²  Sophia Roßkopf²  KlaraMarie Eichholz²  KatarinaJulia Diemer²  Dorothee Winterberg³  DenisMartin Schewe³ 

[1] Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, University Hospital, LMU Munich, 81377 Munich, Germany;Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany;Pediatric Hematology/Oncology, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany;

关键词: antibody therapy;    cluster of differentiation 19 (CD19);    CD19;    Fc fragment crystallizable (Fc);    Fc engineering;    complement-dependent cytotoxicity (CDC);   

DOI  :  10.3390/antib9040063

来源: DOAJ

【 摘 要 】

Background: Native cluster of differentiation (CD) 19 targeting antibodies are poorly effective in triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are crucial effector functions of therapeutic antibodies in cancer immunotherapy. Both functions can be enhanced by engineering the antibody’s Fc region by altering the amino acid sequence (Fc protein-engineering) or the Fc-linked glycan (Fc glyco-engineering). We hypothesized that combining Fc glyco-engineering with Fc protein-engineering will rescue ADCC and CDC in CD19 antibodies. Results: Four versions of a CD19 antibody based on tafasitamab’s V-regions were generated: a native IgG1, an Fc protein-engineered version with amino acid exchanges S267E/H268F/S324T/G236A/I332E (EFTAE modification) to enhance CDC, and afucosylated, Fc glyco-engineered versions of both to promote ADCC. Irrespective of fucosylation, antibodies carrying the EFTAE modification had enhanced C1q binding and were superior in inducing CDC. In contrast, afucosylated versions exerted an enhanced affinity to Fcγ receptor IIIA and had increased ADCC activity. Of note, the double-engineered antibody harboring the EFTAE modification and lacking fucose triggered both CDC and ADCC more efficiently. Conclusions: Fc glyco-engineering and protein-engineering could be combined to enhance ADCC and CDC in CD19 antibodies and may allow the generation of antibodies with higher therapeutic efficacy by promoting two key functions simultaneously.

【 授权许可】

Unknown