Part 1: Introduction to agonist antibody therapies.
The headlines tell the tale: Pfizer initiates a Phase 1 with anti-4-1BB, Medimmune/AZN advances anti-OX40, Celldex pairs anti-CD27 with Bristol’s nivolumab, and Merck plans a Phase 1 study for anti-GITR. Its very early days for this collection of targets, and I think many people find them difficult to differentiate. As always, differentiation will come in the clinic, but this is a long road. We plan to briefly summarize the biology of this family of therapeutic targets and review their clinical application to date.
First of all it’s worth noting that these 4 TNF receptor superfamily members are closely related, as shown here based on sequence alignment of the cysteine-rich domains as analyzed by the late Jurg Tschopp and his colleague Pascal Schneider, our great friends from the early days of TNF and TNR receptor superfamily discovery:
The image is from Bodmer et al. 2002 TiBS 27: 18 – 26 (Jean-Luc Bodmer was a member of Jurg’s group at the University of Lausanne). This analysis aligns the CD27, 4-1BB, OX40 and GITR receptors with CD30 and CD40, and places these next to the BAFF/APRIL receptors BCMA, TACI and BAFF-R. Not all alignments produce the same neighbors but multiple independent analyses, including one published by Alexey Lugovskoy (Merrimack Pharma) and myself in 2003, cluster these 4 critical receptors.
Notably, these are all primarily T cell receptors, although that observation alone oversimplifies the biology quite a bit. The table below summarizes the expression pattern of the receptors and their ligands.
All 4 receptors function to promote and expand CD4+ and/or CD8+ T cell activity. Most also act on NK cells and NKT cells. To some variable extent, signaling through these receptors blunts T regulatory cell (Treg) activity as we will discuss for each target. The therapeutic hypotheses are therefore that activation of these pathways by agonist antibodies, alone or in combination, will trigger anti-tumor immune responses by supporting effector T cell activity and limiting Treg activity. A good set of hypotheses supported by robust preclinical data sets and some early clinical trial work. We’ll look more closely at the development of antibodies to these targets in part 2.