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Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.
The company will in-license a novel antibody, which has a conformation that is associated with increased therapeutic efficacy.
BioInvent International AB announced on Dec. 10, 2015 it is licensing the novel monoclonal antibody (mAb) IgG2B from The University of Southampton and the company Cancer Research Technology. Researchers from the University of Southampton and Cancer Research Technology determined in early 2015-in an article published in Cancer Cell-that engineering the shape of a mAb can help increase its potency. They noted that their novel antibody shape, which they called a locked B structure, was associated with higher levels of mAb potency. The change in shape of the mAb allowed it to function without the help of other immune cells.
The increase in the mAb’s efficacy is due to interaction differences in the Fc receptor region of the molecule, which influence events downstream of initial antigen engagement, according to researchers. Most antibodies need to be crosslinked to promote receptor clustering and activation, the study’s lead author, Ann White, told BioPharm International, and in-vivo crosslinking is mediated by FcγRIIB expressed on immune cells. The IgG2 antibodies in the Cancer Cell study were able to stimulate signaling through their receptor targets without a requirement for FcγRIIB cross-linking, White said.
Authors examined the immunomodulatory activity of human IgG isotopes using mAbs against a number of human costimulatory receptors that are currently being investigated as promising therapeutic targets (such as CD40 and CD28). The scientists were able to pinpoint and "lock" the disulfide bonds in the h2 hinge and CH1 domains of the mAbs and measure the ability of the engineered mAbs to stimulate human B-cell activation and proliferation in vitro.
The investigators concluded that their h2-engineered mAbs conferred greater immunostimulatory activity (as measured by CD8 T-cell response), which was associated with increased therapeutic activity.
The findings were surprising, the authors noted: “Finding an Ab format that can achieve such crosslinking without FcγR engagement is both unexpected and unexplained, as almost all agonistic mAbs described to date ... require FcγR crosslinking for activity." The locked nature of the h2 hinge-because of its lattice of rigidity-may facilitate better downstream signals, the author suggested. They also mentioned the study findings could be due to the ability of h2B to stabilize receptors in pre-existing clusters.
“The data presented have profound implication for the development of agonistic mAb-based therapeutics,” the authors wrote. “Equipped with these insights, it should be possible to manipulate the disulfide bond configuration of h2 to control the activity and toxicity of mAbs directed against a range of immune receptors, thereby permitting the fine-tuning of biological function and the subsequent development of novel therapeutics independent of FcγR interaction.”
Sources: Cancer Cell, BioInvent