Abstract
Antibody therapeutics offer effective treatment options for a broad range of diseases. One of the greatest benefits of antibody therapeutics is their extraordinarily long serum half-life, allowing infrequent dosing with long-lasting effects. A characteristic of antibodies that drives long half-life is the ability to interact with the recycling receptor, FcRn, in a pH-dependent manner. The benefit of long half-life, however, carries with it liabilities. Although the positive effects of antibody therapeutics are long-lasting, any acute adverse events or chronic negative impacts, such as immunosuppression in the face of an infection, are also long-lasting. Therefore, we sought to develop antibodies with a chemical handle that alone would enjoy the long half-life of normal antibodies but, upon addition of a small-molecule antidote, would interact with the chemical handle and inhibit the antibody recycling mechanism, thus leading to rapid degradation and shortened half-life in vivo. Here we present a proof of concept study where we identify sites to incorporate a non-natural amino acid that can be chemically modified to modulate FcRn interaction in vitro and antibody half-life in vivo. This is an important first step in developing safer therapeutics, and the next step will be development of technology that can perform the modifying chemistry in vivo.
Highlights
Therapeutic antibodies continue to push the boundaries of disease treatment through specificity, efficacy, functionality, and potency [1, 2]
We have introduced a non-natural amino acid3 into the Fc domain of a therapeutic antibody [18, 19]. This nnAA can be incorporated site at an amber stop codon by using the orthogonal pyrrolysyl-tRNA synthetase and its cognate tRNA from Methanosarcina mazei [20, 21]
To modulate FcRn binding, we evaluated the co-crystal structure of the antibody constant domain and human FcRn to identify amino acids at the binding interface that could accommodate a non-natural amino acid (Fig. 2) [24]
Summary
Therapeutic antibodies continue to push the boundaries of disease treatment through specificity, efficacy, functionality, and potency [1, 2]. In this work we propose to exploit the FcRn salvage mechanism to modulate antibody half-life with the goal of mitigating risks associated with therapeutic antibodies. By on-demand blocking of the FcRn binding site of the therapeutic antibody with an antidote, the FcRn recycling mechanism would be inhibited, and the half-life of the therapeutic antibody would be significantly reduced (Fig. 1). To achieve this goal, we have created a chemically addressable FcRn modulator. FcRn therapeutic antibody serum protein antidote modate the nnAA AzK incorporation while maintaining native FcRn affinity, retaining natural half-life. We evaluated proof-ofconcept antidotes that can block FcRn binding, demonstrating increased antibody clearance in vivo
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