Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review

Abstract

Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc–FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG–FcRn interactions and their application in human therapeutics.

Matrixed CDR grafting: A neoclassical framework for antibody humanization and developability

“…Antibody engineering seeks to globally optimize a sequence from multiple different perspectives ( 20 , 39 ). Molecular properties including manufacturing, physicochemical stability, affinity, and specificity are considered in tandem with more physiological implications such as immunogenicity, effector function, and half-life extension ( 19 , 40 , 41 , 42 , 43 , 44 ). Humanization of antibody sequences from wildtype platforms adds another layer of complexity to this challenging task.…”

Finding the Right Heavy Chains for Immunostimulatory Antibodies

“…One could imagine a finer tuning of the Fc region to increase the binding to some FcγR and not others. In immunostimulatory antibodies, it is also surprising that none of the mutations described and clinically used to increase the binding to FcRn at pH6 and to increase the half-life of IgG [ 60 ] have not been introduced in the Fc region. This could be because these drugs are very potent immunostimulants and that the reasonable choice is not to have an extended duration of action in case of adverse effects.…”

Antibody–Drug Conjugates: The Dynamic Evolution from Conventional to Next-Generation Constructs

“…These include inhibition of target receptor downstream signaling pathways (e.g., regulating cell proliferation, metastasis, and survival) via the Fab (fragment antigen binding) region or Fc (fragment crystallizable)-mediated killing mechanisms like antibody-or complement-dependent cellular cytotoxicity (ADCC and CDD, respectively) and antibody-dependent phagocytosis (ADP), which directly engage innate immune or complement effectors. From this perspective, novel trends in ADC optimization intentionally exploit or modulate these mAb natural functions via Fc engineering to fine-tune the therapeutic index [5,11,12]. For example, Fc enhancement has demonstrated its benefit with the approval of an Fc-engineered afucosylated mAb-based ADC, namely, brentuximab vedotin (Blenrep ® ) [5,13].…”