Merck Used cryo-EM to Gain Insight Into Mechanism of Action by Imaging Structures of Inhibitory Antibodies Complexed with Arginase 1.
Our Perspective:
In this paper, Merck partnered with us to use cryo-EM to gain insight into mechanism of action by imaging structures of inhibitory antibodies complexed with arginase 1. Human Arginase 1 (hArg1) is an important therapeutic target for the treatment of various cancers, nervous system dysfunction, and cardiovascular dysfunction and diseases. While all published reports on inhibitors of hArg1 have focused on the discovery and optimization of small molecules, this paper shows the use of antibodies to target and neutralize the function of hArg1.
Studies that identify and refine antibodies as therapeutic treatments are proliferating, leading to future success in the treatment of diseases in the immuno-oncology space and beyond. Cryo-EM is the enabling technique for these breakthrough studies. When also considering the knowledge gained through use of inhibitory antibodies as probes for new inhibitor molecule design, the determination of cryo-EM derived antibody: enzyme structures is important and will further the development of therapeutics in the future.
The paper, published in Nature Communications Biology concludes:
- Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size.
- We successfully identified and characterized five potent full-length anti-hArg1 antibodies. Enabled by cryo-electron microscopy (cryo-EM) studies, we present here the full structural analysis of five large hArg1:mAb macromolecular complexes, each of which is composed of trimeric hArg1 bound to potent anti-hArg1 antibodies. These mAbs differ both in epitopes and constant domain backbones, leading to varying complex structures.
- The availability of these high-resolution three-dimensional complexes allows for elucidation of the structural details of the antibody-antigen complex and facilitates the design of future inhibitory antibody variants against hArg1.
- In addition, the insights on steric occlusion of enzyme active sites is applicable to numerous enzymatic proteins and could serve as a framework for targeting other enzymes present in the extracellular compartment. Specifically, using antibodies as probes for new means of inhibition assists in the expansion of inhibitor chemical diversity.
- These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general.
- The identification and characterization of highly selective inhibitory antibodies can be used as a discovery tool in the pursuit of enzymatic inhibitors that fall outside of the traditional methods of enzymatic inhibition including allosteric mechanisms, and substrate, transition state, or product mimicry.
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