Antidromic strategies to target RASopathies

Ras proteins are hubs of various signaling pathways activated by external stimuli and control gene expression and regulate cell proliferation, differentiation and survival. Strategies to target RAS directly in malignant cells include small-molecule inhibitors, intrabodies crossing the plasma membrane and binding RAS in the cytosol or targeting RAS mutant peptide in the HLA complex present on the cell surface via HLA-restricted antibodies. However, current RAS targeting antibodies have major drawbacks.

It was discovered that on certain malignant cancer cells RAS proteins are expressed in very small quantities on the outer side of the cell membrane. Aberrant RAS expression was found on CD138+ cells from multiple myeloma (MM) patients using mass spectrometry and low expression of RAS was found on viable leukeimc cells. Different antibodies, targeting all three RAS proteins (KRAS, NRAS and HRAS), were recombinantly produced to target bispecific T cell engagers . These PCC (protein catalyzed capture) antibodies effectively target lowly expressed extracelullar RAS antigens on MM cells constructs were shown to redirect cytotoxic T cells against a human pancreatic tumor cell line in vitro.