Conversely, mAb can induce cytotoxicity through the recruitment of C1q and subsequent activation of the classical complement cascade. The Fc-domain of hIgG1 interacts with Fc gamma receptors (FcγR), where engagement and signalling on immune effector cells elicit antibody-dependent cellular cytotoxicity (ADCC) 4, 5 and/or antibody-dependent cellular phagocytosis (ADCP) 6. They can induce cell death directly through Fab-mediated antigen binding (direct cell death (DCD)) 2, 3 or Fc-mediated effector functions. Rituximab and next-generation anti-CD20 antibodies, such as obinutuzumab, are used front-line in the treatment of CD20+ B-cell lymphomas and leukaemias 1, employing multiple effector mechanisms to eliminate cancer cells.
The first mAb approved for the treatment of haematologic cancer was the anti-CD20 chimeric human (h)IgG1 rituximab (Rituxan, Mabthera). Monoclonal antibodies (mAb) display utility in the treatment of several cancer indications. Hence, C575S-tailpiece technology represents an alternative format for promoting on-target hexamerisation and enhanced CDC. C575S mutant tailpiece antibodies displayed increased complement activity only after target binding, in-line with the concept of ‘on-target hexamerisation’, whilst retaining efficient in-vivo efficacy and augmented target cell killing in the lymph node. Mutation of the penultimate tailpiece cysteine to serine (C575S) ablated spontaneous hexamer formation, but facilitated reversible hexamer formation after concentration in solution. Fusion of the C-terminal tailpiece of IgM promoted spontaneous hIgG hexamer formation, resulting in enhanced C1q recruitment and complement-dependent cytotoxicity (CDC) but with off-target complement activation and reduced in-vivo efficacy. Herein is described an approach to exploit the tailpiece of the naturally multimeric IgM to augment hexamerisation of IgG. Optimal C1q interaction is achieved through hexameric Fc:Fc interactions at the target cell surface. The majority of depleting monoclonal antibody (mAb) drugs elicit responses via Fc-FcγR and Fc-C1q interactions.
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