Immune Propulsion

Our technology exploits the pivotal intersection of molecular immunology and microbiology through the lens of a unique protease derived from S. pyogenes.

Recent advances in molecular immunology and microbiology interweave in the present proposal. Especially pertinent is the recently described IdeS* protease which is expressed by S. pyogenes. Through its specific cleavage of host IgGs at the gly236 – gly237 bond in the hinge (even at only one of the replicate chains), IdeS causes a nearly full disablement of host antibody functions. –a seemingly unmanageable defense. Yet human hosts respond and counter with their own defense. Specifically, when the cryptic epitope is revealed in IgG at the cleavage point, widespread anti-hinge antibodies of the host bind to that site (all healthy humans tested possess such IgGs).  Also of interest was that these anti-hinge Abs are largely made up of the potently cytotoxic IgG3 isotype. By binding to the “damaged” primary Ab, these IgG3s not only restored killing functions to IdeS-cleaved, cancer-cell-bound Abs, they extended the action well beyond that of an intact cell-bound Ab. We next assessed the possibility of redirecting this immune pathway –normally directed against a bacterial target –to cancer cells with surprising results. In one test, IdeS-cleaved rituximab achieved comparable killing (Ramos cells) at a 100-X lower concentration compared to intact rituximab. A similar trend was seen with other anti-tumor mAbs (e.g. trastuzumab, cetuximab) with different target cell lines.  The generality of the phenomenon points to an unexpected new platform for cancer treatment.  The cell-based testing described above were composed of human cancer cell lines, pooled human IgG (IVIg) as the anti-hinge Ab source and isolated human natural killer (NK) cells. While persuasive from an in vitro perspective, an in vivo verification was clearly needed. Here, cynomolgus monkeys provided an unambiguous confirmation and simplification. Specifically, the animals provided circulating B-cells as the clearance end-point, as well as their own intrinsic anti-hinge Abs and immune effector components (NK cells and/or complement). The result was that B-cell clearance was not only achieved with the “proteolyzed” form of rituximab, but the extent and onset exceeded that of the intact mAb. The bacterial protease can be seen as the catalytic stimulus, but the host’s immune system supplied the rest.

The restoration of cell killing to an IdeS-disabled anti-cancer mAb when engaged by host anti-hinge antibodies could provide the first application of the anti-hinge technology. But the potential for amplification of function to autologous anti-cancer antibodies represents another level that may address frustrating therapeutic challenges within the tumor environment. Tumor cells are known to express varying levels of antigen(s) among cells and over time. The body’s own tumor surveillance system contains antibodies that are polyclonal with different specificities, isotypes. and aspects of presentation on cell surfaces. This complexity may well contribute to cancer’s resilience and evasion of host immunity. The anti-hinge approach, with its high content of potent IgG3 Abs, can be seen as greatly simplifying heterogeneity. Specifically, all bound anti-tumor antibodies, regardless of their epitope specificity, get converted to the same hinge cleavage point target with the ensuing tumoricidal actions greatly aided by the IgG3 isotype.