Immune checkpoint inhibitors: a patent review(2010-2015)

The ability of the immune system to detect and eliminate cancer was first proposed over 100 years ago. Since then, T cells reactive against tumor-associated antigens have been detected in the blood of patients with many different types of cancers, suggesting a role for the immune system in fighting cancer.

Innate and adaptive immunity maintains effector cells such as lymphocytes and natural killer cells that distinguish normal cells from “modified” cells as in the case of tumor cells. However, most often tumor cells are able to evade immune recognition and destruction. The mechanisms of tumor escape are numerous, but the immunosuppressive action of coinhibitory molecules has emerged this last decade as the most attractive one for imaging new treatments of cancer. Activation of lymphocytes is indeed regulated by both costimulatory and coinhibitory molecules, belonging to the B7/CD28 superfamily (also known as the Immunoglobulin (Ig) superfamily) and the TNF/TNFR superfamily. The balance between these signals determines the lymphocyte activation and consequently regulates the immune response. These costimulatory and coinhibitory molecules were called “immune checkpoints”. Examples of immune checkpoints include PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39.

Accordingly, the term “immune checkpoint inhibitor” refers to any compound inhibiting the function of an immune checkpoint and typically include peptides, nucleic acid molecules and small molecules, but currently preferred immune checkpoint inhibitors are antibodies. The immune checkpoint inhibitor is administered for enhancing the proliferation, migration, persistence and/or cytotoxic activity of T cells in a subject and in particular the tumor-infiltrating of T cells. The two coinhibitory molecules that have been the most extensively studied and for which antagonist monoclonal antibodies (mAbs) already tested in clinical trials are cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1). Historically, the monoclonal antibodies inhibiting CTLA-4 (ipilimumab) or PD-1 (nivolumab, pembrolizumab) have indeed demonstrated significant efficacy and are already approved, and expected to be blockbusters in the future. The cancer immunotherapy market will achieve sales of more than 13 billions USD in 2023, of which these sales will be dominated by immune checkpoint inhibitors. Not surprisingly, many companies have therefore developed important patent activities in this field. This article reviews the patent landscape over the period 210-2015, and discusses key players related to immune checkpoint inhibitors.

Programmed cell death protein 1 (PD-1, also known as CD279) is a cell surface receptor from the immunoglobulin superfamily that is expressed on T cells and pro-B cells. PD-1 acts as an immune checkpoint, which upon binding of one of its ligands, PD-L1 or PD-L2, inhibits the activation of T cells. Therefore overexpression of PD-L1 or PD-L2 in the tumoral microenvironment leads to the inhibition of the intratumoral immune responses. Anti-PD- 1/PD-L1 antibodies interfere with ligand binding, and thus inhibit the deactivation of T cells. This axis is probably the most active one in the development of immune checkpoint inhibitors and many patent applications related to antibodies were filed during the period.

Table 1 shows some selected patent applications related to such antibodies. Dana Farber Institute is still the most active academic center with at least three patent applications filed during the period (Table 1). It should be noted that Gordon Freeman of Dana-Farber Cancer Institute identified ligands to PD-1 and is named inventor in about 33 patent families having the terms “PD-1“, “PD1“ “programmed cell death“ or “B7” in their claim. Medimmune, which completed its acquisition of Amplimmune in 2013, was probably the most active company with at least 4 international patents applications filed over the period and related to anti-PD-1 antibodies (Table 1). It is anticipated that the PD-1/PD-L1 class will gain approvals for multiple tumor types and that this class will be the most commercially successful immuno-oncology class over the next 10 years. The positive clinical results that have been achieved in non-small cell lung cancer (NSCLC) have caused excitement because they have shown that PD-1 inhibitors are active in solid tumors outside of melanoma. Beyond pembrolizumab and nivolumab, the next most advanced drugs in the PD-1/PD-L1 class are RG7446 (Roche) and MEDI-4736 (AstraZeneca). RG7446 is in Phase III development for NSCLC (ClinicalTrials. gov identifier: NCT02008227) and MEDI-4736 is in Phase III development for NSCLC ( identifier: NCT02125461). In the future, PD-1/PD-L1 inhibitors will probably form the backbone of most immuno-oncology drug combinations, which is why the patent activities for different combinations have been very intense during the period (Table 2). Genentech and Hoffmann La Roche filed at least 7 international patent applications over the period. The PD-1/PD-L1 inhibitors make indeed an excellent choice as a drug to pair with other immuno-oncology drugs or other targeted therapies because of their efficacy and relatively manageable toxicity. The results from the Phase II CheckMate-069 trial have Downloaded by [McMaster University] at 06:02 08 April 2016 4 demonstrated that the combination of nivolumab and ipilimumab achieved a high response rate and a high percentage of complete responses in melanoma patients. This combination will likely be the first PD-1-based immunooncology combination to reach the market but it certainly will not be the last. In addition to combinations with other checkpoint inhibitors, the PD-1/PD-L1 inhibitors are being investigated in combination with tumor necrosis factor receptors (TNFRs), adoptive T-cell therapies, cancer vaccines, and a variety of other immunooncology drugs. It is noticeable that several patent applications claim the combination between a PD-1 inhibitor and a VEGFR inhibitor. It is still too early to say which combination approach will be the most effective, but the direction of research and the available data suggest that future immuno-oncology drug combinations are likely to consist of a PD-1/PD-L1 inhibitor paired with something else.



Matthieu Collin. Expert Opinion on Therapeutic Patents.