The Devel­op­ment of USP7 Inhibitor for Can­cer Immunotherapy

Ubiq­ui­tin-spe­cif­ic pro­tease 7 (USP7) reg­u­lates the sta­bil­i­ty and fate of many pro­teins, there­by influ­enc­ing cel­lu­lar process­es. Ele­vat­ed lev­el of USP7 in can­cer con­tributes to tumor pro­gres­sion by mod­u­la­tion of tumor microen­vi­ron­ment. USP7 has a vari­ety of sub­strates, includ­ing MDM2 (Murine dou­ble minute 2) and the tumor sup­pres­sor p53 — well known tar­gets in can­cer drug devel­op­ment. We have explored USP7-MDM2-p53 path­way in the con­text of immunomodulation.

After admin­is­ter­ing OAT-4828, we observed a sig­nif­i­cant reduc­tion in tumor vol­ume in syn­gene­ic mouse mod­els of colon, melanoma can­cer, and leukemia. This reduc­tion was asso­ci­at­ed with a sub­stan­tial increase in T cell acti­va­tion, as evi­denced by high­er lev­els of CD69 and CD44, as well as increased pro­duc­tion of Granzyme B and IFN‑γ. Anti­tu­mor activ­i­ty of OAT-4828 was improved when com­bined with anti-PD‑1 anti­bod­ies, while the T cell deple­tion com­plete­ly abro­gat­ed the ther­a­py outcome.

OAT-4828 caused increased pro­duc­tion of IL‑2 and upreg­u­la­tion of CD25 and CD69 in human T cells, which was asso­ci­at­ed with MDM2 down­reg­u­la­tion and p53 sta­bi­liza­tion. Sim­i­lar­ly, inhi­bi­tion of USP7 lead to down­reg­u­lat­ing MDM2 in macrophages, inhibit­ing their M2-like func­tions. These results indi­cate that the main mech­a­nism of action of OAT-4828 is based on the acti­va­tion and improved cyto­tox­ic func­tions of T cells and pro­mot­ing anti-can­cer activ­i­ty rel­e­vant to the tumor microenvironment.

USP7-MDM2-p53 is impli­cat­ed in func­tion of immune cells and tumor microen­vi­ron­ment. Alto­geth­er we con­firm USP7 as an attrac­tive tar­get for can­cer immunother­a­py and present the ratio­nale for the devel­op­ment of USP7 inhibitors for clin­i­cal use.