Primary and acquired resistance to anti-cancer antibody immunotherapies presents significant clinical challenges. Here we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the immunoglobulin G1 (IgG1) hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMPs), IdeS exposes a hinge neo-epitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost ADCC functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc engineered, proteinase-resistant version of mAb2095-2 rescued trastuzumab anti-tumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, while trastuzumab alone showed significantly reduced anti-tumor activity in the same model. Consistently, an Fc engineered proteinase-resistant version of trastuzumab also greatly improved anti-tumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc engineered monoclonal antibody against the hinge neo-epitope and to overcome cancer evasion of antibody immunity.
- Received August 21, 2014.
- Revision received December 11, 2014.
- Accepted December 11, 2014.
- Copyright © 2014, American Association for Cancer Research.