Living in LALA land? Forty years of attenuating Fc effector functions

Abstract

The Fc region of antibodies is vital for most of their physiological functions, many of which are engaged through binding to a range of Fc receptors. However, these same interactions are not always helpful or wanted when therapeutic antibodies are directed against self-antigens, and can sometimes cause catastrophic adverse reactions. Over the past 40 years, there have been intensive efforts to "silence" unwanted binding to Fc-gamma receptors, resulting in at least 45 different variants which have entered clinical trials. One of the best known is "LALA" (L234A/L235A). However, neither this, nor most of the other variants in clinical use are completely silenced, and in addition, the biophysical properties of many of them are compromised. I review the development of different variants to see what we can learn from their biological properties and use in the clinic. With the rise of powerful new uses of antibody therapy such as bispecific T-cell engagers, antibody-drug conjugates, and checkpoint inhibitors, it is increasingly important to optimize the Fc region as well as the antibody binding site in order to achieve the best combination of safety and efficacy.

Keywords: Fc receptor; Fc region; antibody engineering; therapeutic antibody.

FIGURE 1

Diagram of human Fcγ receptors showing their main interactions with human IgG subclasses and expression on cells of the immune system. Alleles of FcγRIIa (131H and 131R), FcγRIIIa (158F and 158V), and FcγRIIIb (NA1 and NA1) differ in their affinity for IgGs and Fc variants.

FIGURE 2

Extract from the TGN1412 Investigator's Brochure showing the high levels of INFγ, TNFα and especially IL2 which are released following incubation of T cells with immobilized TGN1412. This is one of the figures redacted from a version of the brochure that was made available to the public and the expert panel. It was only released by the MHRA following years of litigation by the Information Commissioner and others and has hitherto not been published.

FIGURE 3

Cumulative use of different variants for Fc silencing in antibodies and Fc fusion proteins assigned an international nonproprietary name (INN). By far the most commonly used is wild‐type IgG4.

FIGURE 4

Protease cleavage sites in the hinge region of human IgG1.