Currently, Orpheus LLC has characterized and developed four PantIds®, each with its own unique indications, as shown in Figure 3. Three of these PantIds® — those containing PD-L1, PD-1, and CTLA-4 sequences — are designed to ameliorate the adverse effects of cancer immunotherapy, specifically, the autoimmune reactivity elicited by certain cancer immunotherapeutics. Additionally, these three PantIds® are indicated in patients with rampant autoimmunity caused by antibodies to immune regulatory receptors; in these patients, the immune system’s regulatory systems are blocked by autoantibodies that can be neutralized by our proprietary PantIds®. Our lead indication, however, the treatment of immune-related adverse events (irAEs) caused by PD-L1 blockade cancer immunotherapeutics, which is described in more detail below.
PD-L1 PantId and immune-related adverse events
While chemotherapy, radiotherapy, and surgery remain a mainstay of cancer treatment, recent progress in immunotherapies have spurred the development of numerous therapeutic antibodies that modify patient immune responses to the cancer. Conventional immunotherapeutics include antibodies that directly bind to cancer cells and elicit anti-tumor immune responses. More recently, several novel immunotherapeutic antibodies with an entirely different mechanism have been developed: these antibodies are designed to disinhibit the immune system, unshackling T and B cells from their regulatory constraints to induce cancer cell killing. This class of immunotherapeutics are called checkpoint inhibitors (CIs), which function by blocking regulatory and immunosuppressive “checkpoint” receptors and their binding partners: as a result, immune cells in the tumor tissue ignore portions of the immunosuppressive signaling environment and become activated. For reference, currently approved CIs target CTLA-4, PD-1, and PD-L1, of which only the latter two are considered in this summary. The market for CIs is enormous, at $10.02B, and is expected to grow to $30B by 2026.
Though this novel form of immunotherapy has marked efficacy, a new class of side-effects are associated with the immune system disinhibition caused by CIs—immune-related adverse events (irAEs). In short, irAEs are clinically-induced autoimmune diseases. The removal of immunosuppressive restraints on patient T and B cells results in their rampant response to normal tissue in a subset of patients, resulting in severe inflammation, tissue and organ destruction, and potentially life-threatening conditions. In fact, a significant percent of patients receiving combination CI therapy discontinue treatment due to the severity of irAEs, including 14% of patients receiving combination CTLA-4 and PD-1 CIs in a melanoma trial (Chae et al. 2018). More pertinently for our PD-L1 PantId, 26% of patients treated with PD-1 or PD-L1 inhibitors develop irAEs, with 6% developing severe irAEs (Wang et al. 2017). Additionally, some irAEs are permanent, and continue unabated after treatment discontinuation.
PD-L1 PantId, along with our PD-1 and CTLA-4 PantIds, are the first therapeutic specifically designed to prevent irAEs and mitigate the morbidity and mortality they cause. PD-L1 and PD-1 are a checkpoint ligand-checkpoint receptor pair that play a pivotal role in regulating anti-cancer immune responses. Resultantly, there are three PD-L1 inhibitors, and two PD-1 inhibitors, that are approved by the FDA. This is particularly germane to the development of PD-L1 and PD-1 PantIds, as the potential market for these PantIds exists only to the extent that PD-1 and PD-L1 CIs are approved, utilized in the clinic, and result in irAEs. Based on the prevalence of irAEs among currently approved CIs, the potential market share of the irAE-directed PantIds would be $0.5B-$3B, depending on whether our PantIds are indicated for all irAEs or only severe irAEs. Additionally, this market should exhibit a high rate of projected growth matching that of CI market growth.
Mechanistically, administration of PD-L1 PantId will neutralize PD-L1 inhibitor antibodies, and thereby prevent the irAEs they cause. Due to the long half-life of therapeutic antibodies in patients, and the persistence of irAEs, rapid CI antibody neutralization is the most efficacious method for preventing irAE development and propagation.