Nanobody-Based Targeted Therapy
MPNRF ADVANCING RESEARCH: Nanobody-Based Targeted Therapy
Through a 2022 MPNRF Thrive Initiative award, Najla Arshad, PhD, Yale University School of Medicine, will explore Development of Nanobody-Based Targeted Therapy for Myeloproliferative Neoplasm, with funding for up to two years.
“There is a real need for a therapy that can target and eliminate these diseased cells, to actually cure the disease, rather than just keeping it at bay,” according to Dr. Arshad.
“When a cell turns rogue, it tries to hide from your body’s defense cells. But both the process of going rogue and hiding, ironically, gives these cells distinct features that we can identify and then teach or help the body to identify and get rid of them,” explains Dr. Arshad.
Around a third of MPNs are driven by a mutant protein called calreticulin (CALR). A mutation in CALR (CALR-FS) causes an alteration in the cell surface landscape. Dr. Arshad’s group plans to exploit those changes to develop nanobody-based therapeutics against these CALR-FS mutant MPN cells.
This can be achieved by various methods, she explains, “We are going to use tiny antibodies (first discovered in camels) called nanobodies, that we can now make in the lab. We’re going to try to choose the right ones that can identify the rogue cells to fight the disease and not harm any other cells.”
CALR (CALR-FS) mutations interact with the thrombopoietin growth factor receptor (TPO-R), driving the disease, resulting in a change in the surface of these cells. In addition, MHC-I, a cell surface protein that alerts the immune system to diseased cells by displaying disease-associated peptides, is downregulated, but this is accompanied by a change in the peptides presented.
The team plans to target the pathogenic CALR-FS-TPO-R interaction and MPN-associated peptide-MHC-I complexes, and then other unidentified cell surface alterations.