Following the discovery of antibodies targeting proteins such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1), we are now able to control and empower a patient’s own T cells with the ability to better recognize malignant cancer cells.

In general, one would think that increasing the number of tumor infiltrating lymphocytes (TILs) would lead to better patient outcomes. However, the tumor microenvironment is by far too clever. Tumors establish surrounding conditions to suppress anti-tumor immune responses, in some cases by upregulating immune checkpoint receptors (such as CD80 in the case CTLA-4 and PD-L1 for PD-1). So even if the tumor is heavily infiltrated with lymphocytes, immune checkpoints hit the brakes on the anti-tumor lymphocytes and tumor growth continues unregulated and unchecked. Antagonistic mAbs targeting the CTLA-4 and PD-1 checkpoints (i.e. checkpoint inhibitors) help lift the foot on the brakes, enabling the anti-tumor lymphocytes to carry out their intended functions. This active form of immunotherapy (as opposed to the passive form which consists of targeting proteins on the surface of cancer cells, such as PD-L1) has led to a record number of approved indications for these antibodies when it comes to various forms of cancer.

Beyond these very common targets, scientists have been aiming to develop additional immunotherapies, such as agonistic antibodies raised against costimulatory receptors. Of particular interest is OX40 (CD134), which acts as a marker for activated CD4+ and CD8+ T cells. Originally discovered at Oxford University (hence the OX) through the immunizing of mice with phytohemagglutinin-activated rat lymph node cells, OX40 originally referred to a hybridoma derived monoclonal antibody targeting the then uncharacterized rat protein; 40 simply came about because the discovered antibodies were numbered sequentially from OX1 onwards.

Its ligand, OX40L (CD252), is often expressed on the surface of activated antigen presenting cells (APCs) such as dendritic cells and B cells, and upon interacting with the OX40 receptor, stimulates T cell proliferation and survival. Over time, in vitro experiments have shown that when the human OX40 homologous protein is targeted and activated by agonistic antibodies, T cell differentiation and cytolytic functions increase.

Recently, Bristol-Myers-Squibb (BMS) has taken to studying its fully human agonistic OX40 antibody (BMS-986178) both as a monotherapy, and in combination with approved checkpoint inhibitors such as Yervoy® (ipilumab) and Opdivo® (nivolumab) targeting CTLA-4 and PD-1, respectively.

While mAbs have been successful as monotherapies in some patients and have led to even more favorable results when combined with chemotherapeutic small molecules, antibody combinations are now the name of the game. Via complimentary mechanisms of action, finding the right antibody combinations could help overcome some of their current limitations as monotherapies and tailor a cancer treatment to each patient (in the form of personalized medicine). With only two therapeutic antibody combinations approved (ipilumab and nivolumab being one of them for the treatment of melanoma as well as metastatic non-small cell lung cancer), this new antibody trifecta has held a lot of potential.

Despite successful preclinical studies, which hinted at a synergistic effect between the studied antibody combinations, BMS-986178 showed no improved clinical benefit over those seen from nivolumab with or without ipilumab. Possible explanations as to why the addition of an OX40 agonistic antibody did not improve the overall response rate in patients include less than optimal dosing, poor translation of preclinical findings, or simply poor OX40 expression on the patients’ T cells.

This would not be BMS’s first rodeo when it comes to participant stratification. Early in the PD-1 targeting battle, nivolumab had the upper hand over Merck’s hybridoma-derived blockbuster antibody Keytruda® (pembrolizumab). In 2016, pembrolizumab gained momentum when a certain trial in untreated non-small cell lung cancer proved the drug efficacious; a similar trial for nivolumab had previously failed. Results simply came down to Merck having an improved patient screening and selection system.

With several other OX40 monoclonal antibodies in development from Pfizer (PF-8600), Incyte (INCAGN01949), and Abbvie (ABBV-368), just to name a few, BMS better figure things out quickly.

As the mythological story goes, the Rat (2020) outwitted the Ox (2021) in the Great Race to the Jade Emperor’s party, thus resulting in it being named the first animal of the Chinese zodiac. So, as I am sure we all hope to move on from 2020 and let this Rat run far away from us, we look to the future with a positive sense of direction. Will this year really be the year of the OX? Only time will tell…

Guillaume Trusz

Author Guillaume Trusz

Guillaume Trusz received his B.S. in Molecular, Cell, and Developmental Biology from the University of California, Los Angeles (UCLA) in 2015 and his M.S. in Biomedical Imaging from the University of California, San Francisco (UCSF) in 2018. Prior to working as an Associate Scientist in the Discovery Immunology Group at Curia, Guillaume contributed to various academic and industry related research projects pertaining to small molecules, nanoparticles, as well as biosimilars.

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