While monoclonal antibody (mAb)-based therapies have revolutionized cancer treatment, a significant fraction of patients fail to respond or develop resistance to treatment. There is a need for rational development of drugs that could help boost efficacy, and prevent or overcome antibody drug resistance.
Co-stimulatory immune checkpoint (IC)
Preclinical and limited clinical data has indicated both single agent activity of antibodies to co-stimulatory immune checkpoints, such as 4-1BB, OX40, CD40, and GITR, and complementary effects following combination with checkpoint blocking antibodies e.g., anti-PD-1. Efficacy and safety of immune agonist checkpoint antibodies is regulated by the FcγRs for optimal therapeutic activity.
We are developing antibodies targeting these co-stimulatory and co-inhibitory checkpoints for better cancer treatment, represented by four therapeutic candidate antibodies in development: anti-PD-1 (LVGN3616), anti-CD137 (LVGN6051), anti-CD40 (LVGN7409) and anti-PD-L1-TGFβ bi-specific (LVGN1673).
Fc receptors (FcRs)
Following antibody Fab-binding to target receptors, Fc gamma receptors (FcγRs) interact with the Fc-domain of aggregated antibodies, orchestrating antibody-induced effector cell responses and immunity.
Like the T cell checkpoints, the Fc gamma receptors (FcγRs) fall into either of two functionally distinct groups. Activating FcγR promotes effector cell activation, and immunity. In contrast, inhibitory FcγR blocks cellular activation and down-modulate immune responses. in stark contrast to the multiple inhibitory T cell checkpoints described, only a single inhibitory antibody checkpoint–Fc gamma receptor IIB (FcγRIIB)–is known.
FcγRIIB promotes immune checkpoint receptor extrinsic signaling by facilitating cross-linking and signaling of antibody Fab-targeted receptors. Depending on immune checkpoint receptor function, such signaling may be activating or inhibitory, as has been described for agonistic anti-CD40 (LVGN7409) and agonistic anti-CD137 (LVGN6501) antibodies.
Lyvgen’s xLinkAb™ platform creates agonist antibodies (Abs) with high tumor-localized immunostimulatory activities in the absence of normal tissue toxicity by introducing variations in the constant (Fc) region of candidate Abs.