Poster Presentation 25th Lorne Cancer Conference 2013

Implications of Fc-engineering to a humanised anti-Ley antibody on Fc gamma receptor binding (#234)

Dylan T King 1 , Dahna Makris 1 , Rachael Canfield 1 , Paul A Ramsland 2 , William Furrugia 2 , Bruno Catimel 1 , Andrew M Scott 1 , Ingrid J G Burvenich 1
  1. Ludwig Institute For Cancer Research, Heidelberg, VIC, Australia
  2. Centre for Immunology, Burnet Institute, Melbourne , Victoria, Australia

The interaction between the immunoglobulin G (IgG) Fc region and Fcγ receptors (FcγRs) is the primary mechanism linking antibody-mediated immune responses with cellular effector functions. Enhancement of this interaction through amino acid variation and glycoengineering of the Fc region has provided a way to improve immune effector functions. The majority of this research has been aimed at enhancement of interactions with FcγRIIIa, which is the key mediator in natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC). But as NK cells are poor infiltrators of solid tumours, engineering for additional receptors and their linked effector functions is warranted. A previous study has shown that mutant antibodies with increased affinity for FcγRIIa relative to FcγRIIb have enhanced macrophage phagocytosis of antibody-coated tumour cells. This is mirrored by clinical data showing improved survival in patients possessing the R131 polymorphic FcγRIIa variant, which has higher affinity for IgG class used in therapy. Here, we describe a set of novel hu3S193 Fc variants created through amino acid engineering with altered FcγR binding affinities. These novel variants were first determined by in silico methods from crystal structures and then produced in a mammalian expression system for further analysis. Preliminary binding affinity data for each of the variants is described.