BND-67, a novel antibody agent, is being developed for overcoming PD-1 blockade resistance by targeting soluble CD28, an immune evasion mechanism discovered by Biond scientists.
CD28 is a lymphocyte expressed receptor, known to mediate crucial co-stimulation signals in T cells needed to generate an efficient and durable anti-tumor activity. Biond scientists have discovered a novel regulatory mechanism in the CD28 axis, that involves its shedding from the surface of T cells, leading to a reduced receptor density and accumulation of soluble CD28 decoy receptor. The soluble form of CD28 was found to be a suppressive molecule that reduces the effector function of T cells and attenuate the anti-PD1 activation effect (Illustration 1).
Model describing the immuno-suppressive effect of CD28 shedding: During the activation of T cells, Matrix MetalloProteinases (MMPs) are upregulated (left panel) and fully activated by pro-domain removal. MMPs cleave CD28 at its stalk region (center panel), releasing a dimeric soluble CD28 that acts as a decoy receptor by binding to CD28 cognate ligands, CD80 and CD86 (B7 molecules) on antigen presenting cells (APC). Tumor residing T cells with lower membranal CD28 density and insufficient B7 mediated signaling will fall into anergic state with low capacity to be rescued by anti-PD1 therapy (right panel).
BND-67 is a first in class single-domain VHH antibody, rationally designed to bind the shedding prone region of the CD28 receptor and sterically hinder the access of MMPs to the cleavage site. The small sized antibody is built to increase the density of CD28 on T cells membranes without conferring any agonistic or antagonistic effect, and thus will augment T cells activation and to overcome resistance to anti-PD1 therapy (Illustration 2).