Cancer Immunotherapy Drugs Step on the Gas

Good news! Cancer is history (soon)!

"... A new study ... revealed that a small molecular change in a common immunotherapy antibody might enable it to bind better to certain “gas pedal” receptors, thus accelerating the immune response against cancer. The study ... also shows that adding a second antibody – one that blocks inhibitory receptors – may improve the effectiveness of anticancer treatments. ...
A closer look revealed that, compared with similar cells of other organs, there were many more of these brake pedal receptors on certain immune cells in the tumor’s microenvironment. That phenomenon was observed in human tumors as well. In tumor samples of skin and kidney cancers ... the scientists identified an increased expression of the immune-suppressing receptors. ...
they tried the experiment again, this time giving the mice a combined treatment of avelumab and a second antibody that had been proven to inhibit the immune-suppressing receptors. With the foot lifted from the immune system’s brakes, the cancer treatment was much more effective. ...
“The findings of this research could undergo a rapid transition from the laboratory to the clinic, to improve those drugs already available to cancer patients,” ..."

"Tweaking the scaffold

Immune checkpoint blockade using anti–PD-L1 monoclonal antibodies (mAbs) is used for treatment of multiple cancers. Whether these mAbs have the optimal Fc scaffold to induce Fc-mediated effector functions is unclear. Here, Cohen-Saban et al. investigate how FcγR engagement by anti–PD-L1 contributes to antitumor immunity. They demonstrate that beneficial FcγR signaling pathways are not engaged by FDA-approved mAbs and use two approaches to increase the ratio of activating to inhibitory FcγR pathway activation. Blockade of the inhibitory FcγRIIB in combination with anti–PD-L1 improved antitumor responses. Similarly, afucosylation of the IgG1 Fc region improved antitumor responses, and this was due to alterations in the tumor microenvironment. These findings identify two approaches to improve anti–PD-L1 therapy and suggest that an afucosylated IgG1 scaffold renders anti–PD-L1 mAbs more effective."

From the abstract:

"FDA-approved anti–PD-L1 monoclonal antibodies (mAbs) bear the IgG1 isotype, whose scaffolds are either wild-type (e.g., avelumab) or Fc-mutated and lacking Fcγ receptor (FcγR) engagement (e.g., atezolizumab). It is unknown whether variation in the ability of the IgG1 Fc region to engage FcγRs renders mAbs with superior therapeutic activity. In this study, we used humanized FcγR mice to study the contribution of FcγR signaling to the antitumor activity of human anti–PD-L1 mAbs and to identify an optimal human IgG scaffold for PD-L1 mAbs. We observed similar antitumor efficacy and comparable tumor immune responses in mice treated with anti–PD-L1 mAbs with wild-type and Fc-mutated IgG scaffolds. However, in vivo antitumor activity of the wild-type anti–PD-L1 mAb avelumab was enhanced by combination treatment with an FcγRIIB-blocking antibody, which was co-administered to overcome the suppressor function of FcγRIIB in the tumor microenvironment (TME). We performed Fc glycoengineering to remove the fucose subunit from the Fc-attached glycan of avelumab to enhance its binding to the activating FcγRIIIA. Treatment with the Fc-afucosylated version of avelumab also enhanced antitumor activity and induced stronger antitumor immune responses compared with the parental IgG. The enhanced effect by afucosylated PD-L1 antibody was dependent on neutrophils and associated with decreased frequencies of PD-L1+ myeloid cells and increased infiltration of T cells in the TME. Our data reveal that the current design of FDA-approved anti–PD-L1 mAbs does not optimally harness FcγR pathways and suggest two strategies to enhance FcγR engagement to optimize anti–PD-L1 immunotherapy."

Immunotherapy Drugs Step on the Gas - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries Sometimes anticancer antibodies press on the gas and the brakes at the same time. New research might help them accelerate better

Fc glycoengineering of a PD-L1 antibody harnesses Fcγ receptors for increased antitumor efficacy (open access)

Tissue sample of a particularly aggressive skin cancer reveals immune cells (yellow) that express on their surfaces a “brake pedal” receptor called FcgIIb (purple); cell nuclei are in blue