Novel antibodies targeting immune regulatory checkpoints for cancer therapy

Abstract

Cancers must evade or suppress the immune system in order to develop. Better understanding of the molecular regulation governing tumour detection and effective activation of the immune system (so called immune regulatory checkpoints) has provided new targets for cancer immunotherapy. Therapeutic monoclonal antibodies against these targets are currently undergoing clinical evaluation with more in pre-clinical development; buoyed by the recent licence approval of the anti-CTLA-4 antibody, ipilumumab, for use in melanoma. This article will review the current status of the various antibodies and target molecules being investigated.

Keywords: cancer; immunomodulatory antibodies; immunotherapy; monoclonal antibodies.

Figure 1

Schematic representation of an immune synapse and downstream events. Signal 1 is generated by T-cell receptor (TCR) recognition of peptide antigen presented on major histocompatibility complex (MHC) by antigen-presenting cells (APCs, e.g. dentritic cells) or tumour cells. Signal 2 is provided by co-regulatory (co-stimulatory or inhibitory) molecules interacting with their cognate ligands expressed on APCs. These co-regulatory molecules can be expressed constitutively in naive T-cells (e.g. CD28 and CD27) or induced by TCR engagement leading to expression at different time points of T-cell activation. Signal 3 is mostly provided by cytokines secreted by APCs or other immune cells including CD4 T-helper cells to help regulate the effector differentiation pathway. Successful activation of a naive CD8 T-cell allows survival and proliferation of the reactive clone, allowing their progeny to differentiate into cytotoxic T lymphocytes that kill tumour cells expressing the tumour associated antigen. Unsuccessful activation leads to anergy or deletion of the T-cell. Transient, abortive activation of T-cells leading to deletion or anergy may occur in the context of antigen presentation by immature (or insufficiently activated) dendritic cells. CD40/CD40L and 4-1BB/4-1BBL are known as bi-directional signalling molecules and ligand engagement activates intra-cellular signalling transduction pathways. Furthermore the receptors can also be expressed on the target cell and may play a part in therapy with mAb. LAG3, lymphocyte activation gene 3; TIM3, T-cell immunoglobulin and mucin domain 3; GAL-9, galectin-9; PD-1, programmed death-1; PDL-1, programmed death ligand-1; HVEM, herpes virus entry mediator; BTLA, B and T lymphocyte activator; CTLA4, cytotoxic T-lymphocyte associated antigen 4; VISTA, V-domain Ig suppressor of T-cell activation; TNFR, tumour necrosis factor receptor

Figure 2

Schematic representation of the multiple immunomodulatory receptors that are potential therapeutic targets as monotherapy or combination therapy with immunomodulatory mAbs. T-cell activation refers to the eventual activity of a complex network of different T-cell lineages (e.g. Th1, Th2, Th17, Treg etc) which can have differential expression of checkpoint regulators. APC, antigen presenting cells; CTL, cytotoxic T lymphocytes