Targeting the B7 Family of Co-Stimulatory Molecules

Abstract

As more patient data is cross-referenced with animal models of disease, the primary focus on Th1 auto-reactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of Th17 autoreactive effector cells and the ability of regulatory T cells (Treg) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between Th1/17 effector cells and Treg cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the Th1/17:Treg cell balance is the utilization of blockade and/ or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

“…42 However, almost none of the relevant review articles include BTLA as a B7-H4 receptor. 10,[43][44][45][46][47][48][49][50] Our findings provide additional support for the role of BTLA as a B7-H4 receptor.…”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…Abatacept has been tested in the clinic and has been shown to be effective and safe, and is currently used for treatment of rheumatoid arthritis (RA) [59]; however, importantly, it failed to show efficacy in early-phase trials in multiple sclerosis (MS) and ulcerative colitis [60,61]. This highlights the evolving concept that co-stimulation blockade with abatacept has differential effects, depending upon the type of T-cell response (effective for Th1 responses but perhaps not for Th2 or Th17-mediated disease).…”

Regulation of Immunity by Butyrophilins

“…Specific antibody, or soluble Fc fusion proteins, targeting B7 molecules and their ligands have shown promise, particularly in cancer treatment, by reversing the inhibitory signals to activated T cells that are generated by cancer cells themselves and their tissue microenvironment (1,2). Checkpoint intervention therapies to inhibit inappropriate T cell activation have also been proposed for autoimmune conditions (3,4).…”