It’s hard to imagine a biomedical field that’s not concerned with cell signaling. From immunologists studying GPCRs and neuroscientists investigating amyloid plaques, to cardiologists telling their patients to avoid caffeine, knowing what’s connected to what and which kinases are phosphorylating which others is all part of the daily grind.
At Cambridge Healthtech’s “Discovery on Target” conference, held earlier this month, pathways leading to and coming from PI3 kinase seemed to be in the forefront of many researchers’ minds. Yet, generating tools to assess and manipulate the status of all sorts of pathways—from those involved in cancer to those responsible for addictive behavior—was of interest no matter what your favorite signaling molecule.
It’s notoriously difficult to generate functional antibodies against complex cell-surface molecules. Antibodies are typically generated against “some kind of artificially expressed and folded GPCRs that don’t always have their native conformation,” remarked Sergej Kiprijanov, Ph.D., vp of research and preclinical development at Affitech.
Affitech wanted to antagonize GPCRs involved in cancer progression and inflammation. Using its cell-based antibody selection (CBAS) technology it screened its massive phage-display human antibody library against receptors (such as the CCR4 and CXCR4 chemokine receptors) expressed on the cell surface in their natural conformation, and identified several candidates able to impact the ability of these receptors to signal.
In the most advanced of six anti- GPCR programs, for example, an anti-CCR4 antibody was found that can deliver a strong response against CCR4+ tumors in xenografts. At the same time, the antibody is able to target CCR4+ regulatory T cells that can inhibit a robust imm?une response against the tumor.
Because of redundancy in the system, one chemokine receptor may have several natural ligands. So, unlike targeting the chemokines themselves, “by blocking the receptor with the same compound you can abolish the signal provided by three or four different chemokines,” explained Dr. Kiprijanov.