Harnessing the body’s immune system to combat cancer has been a therapeutic strategy decades in the making. First considered in the 1970s, it was hypothesized that antibodies could be created to target tumor associated antigens, and thereby trigger an immune response that would destroy the tumor. However, despite significant excitement about the technology, it was not until 1997 that the first monoclonal antibody immunotherapy (Rituximab) was commercialized by IDEC Pharmaceuticals. Since then, another 11 antibodies have been approved as anti-cancer agents, and immunotherapy has become a mainstay in the treatment of certain forms of cancer. However, safety drawbacks have limited the number of therapeutic antibodies developed successfully, and present a major challenge to the tolerability of approved agents.
Cytomx enters the space with a an approach that aims to address key toxicities of immune-oncology therapeutics. Unlike traditional antibodies, which will bind their targets wherever they occur throughout the patient’s body, Cytomx has developed a class of produg-like antibody, termed “probody”, that is activated only at the site of the tumor. Probodies contain masking peptides that block recognition and binding to their target antigens. In the tumor microenvironment, where certain proteases are highly expressed, the masking peptide is cleaved off, allowing the probody to engage its target. Studies in rodents and non-human primates have suggested order of magnitude improvements in the therapeutic indices of probodies versus commercialized antibody therapies.
The advantage of the probody approach is twofold. First, it allows for the targeting of antigens that are strongly, but not exclusively expressed on tumor cells. Such antigens are not durable with conventional antibodies due to the induction of systemic toxicities. The second advantage of the probody strategy is that it allows for an improvement in therapeutic index for the vast majority of antibodies in development or in the clinic. This broad applicability has been demonstrated in the formation of partnerships with Bristol-Myers Squibb (Ipilimumab probody and additional targets), Pfizer (Cetuximab probody and additional targets), Immunogen (probody drug conjugates), and MD Anderson Cancer Center (probody CAR-NK cell therapies). Cytomx’s lead programs, slated to enter clinical trials in 2016 and 2017, include a PD-L1 checkpoint probody, and a CD166 (widely expressed antigen) probody.
