Combined Therapy of CTLA-4 and OX40

Background

Co-stimulatory OX40 and co-inhibitory CTLA-4 receptors promote or restrict T cell activation, respectively, and play an important role in regulating the course of an immune response. Antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the brakes on T cells to augment tumor immunotherapy. Ligation of the co-stimulatory molecule OX40 with an agonist anti-OX40 mAb enhances anti-tumor immunity by augmenting T cell differentiation. Unfortunately, monotherapy with these agents has limited therapeutic benefits against poorly immunogenic murine tumors. In recent years, studies revealed that combined anti-CTLA-4/anti-OX40 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell-dependent manner.

Case 1: Combined OX40 plus CTLA-4 Blockade

Previous studies demonstrated that systemic administration of anti-CTLA-4/anti-OX40 mAb, in the absence of toll-like receptor (TLR) agonists, significantly improves survival and primary tumor regression in sarcoma tumor-bearing mice and the poorly immunogenic mouse model of prostate cancer. Monotherapy with either agent alone was insufficient to enhance survival. Combination therapy augmented the frequency of proliferating polyclonal effector CD8 T cells.

Fig.1 Combined anti-OX40/anti-CTLA-4 mAb immunotherapy enhances tumor regression and survival. (Linch, 2014)

Case 2: Combinational Therapy Reverses T-cell Anergy and Promotes Survival in Tumor-bearing Mice

In another study, scientists demonstrated that anti-OX40/anti-CTLA-4 immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Relative to combination therapy alone, vaccination with combination therapy not only restricted Th2-cytokine production by CD4 cells but also enhanced IFNγ production by CD8 and CD4 cells. Notably, in a spontaneous model of prostate cancer, vaccination with combination therapy reversed anergy and improved the expansion and function of CD8 T cells recognizing a tumor-associated antigen.

Fig.2 Combination therapy boosts the expansion, function, and persistence of memory CD8 T cells. (Linch, 2016)

CTLA-4 x OX40 Bispecific Antibody

The CTLA-4 x OX40 targeting bispecific antibody can be generated by linking an optimized version of the Ig-like V-type domain of human CD86, a natural CTLA-4 ligand, to an agonistic OX40 antibody. This bispecific antibody induces T-cell activation and Treg depletion in vitro. By targeting CTLA-4 and OX40 simultaneously, the bispecific antibody is directed to the tumor area, where it induces enhanced immune activation. Treatment with bispecific antibody reduces tumor growth and improves survival in several syngeneic tumor models, including bladder, colon, and pancreas cancer models.

Creative Biolabs is ready to provide the customized CTLA-4/OX40 targeted antibody and small molecule drug development services. Our experienced scientists also provide various laboratory assays as well as professional technical support. Please feel free to contact us for more details.

References

1. Linch, S. N.; Redmond, W. L. Combined OX40 ligation plus CTLA-4 blockade: more than the sum of its parts. Oncoimmunology. 2014, 3(3): e28245.
2. Linch, S. N.; et al. Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proceedings of the National Academy of Sciences. 2016, 113(3): E319-E327.

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