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

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.