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The initial clinical efficacy of IL7 fusion protein
The initial clinical efficacy of IL7 fusion protein. IL-7 plays a key role in the development and survival of T cells. When the number of T cells is low, the physiological level of IL-7 increases, which stimulates the proliferation of T cells.
However, as a steady-state cytokine, IL-7 levels will not increase significantly under these circumstances, and the recovery of T cell numbers is usually a slow process.
IL-7 acts through the IL-7 receptor (IL-7R), which is expressed on naïve and memory CD4+ and CD8+ T cells. Therefore, IL-7 promotes the proliferation, maintenance and function of key T cell subsets and mediates immune responses. On the other hand, IL-7R is expressed on low-level Treg cells. NeoImmuneTech has made many explorations in IL-7-based treatment programs.
NT-I7 (efineptakin alfa) is a stable and long-acting human IL-7 fusion protein, which can overcome the limitations of human endogenous IL-7. NeoImmuneTech engineered the N-terminal domain of IL-7 to overcome its structural instability and enable large-scale production of NT-I7. A section of Fc is added to the C-terminus of NT-I7, which is a hybrid of IgD and IgG4 subtypes, called hyFc® (hybrid Fc) domain, which prolongs the half-life of IL-7.
NeoImmuneTech announced preliminary NT-I7 (efineptakin alfa) clinical results on ASCO in 2021. “Safety, pharmacokinetics, pharmacodynamics profiles and preliminary antitumor activity of phase 1b/2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: The phase 1b data report.”
Enrolled 12 patients, 3 dose groups, 480, 960, and 1200 ug/kg. DL1 (n=3), DL2 (n=3) and DL3 (n=6). MTD has not been reached. DL3 reports 1 case of DLT ([G] Grade 3 ALT elevation). Treatment-related adverse events (AEs) occurred in 11 (91.7%) patients, 11 (91.7%) grade 1-2 patients and 4 (33.3%) grade 3 patients; there were no G4 or G5 AEs. Common treatment-related adverse reactions are injection site reactions (n=8, 66.7%), chills (n=7, 58.3%), nausea (n=6, 50%) and fever (n=6, 50%). Preliminary PK analysis showed that at DL3, NT-I7 had Tmax = 24 hours and T1/2 = 123 hours. NT-I7 + pembro induced the proliferation of lymphocytes in peripheral blood in a dose-dependent manner, which increased ~ 3 times at DL3. After the first treatment, the ratio of neutrophils to lymphocytes decreased correspondingly at 14 days.
Overall well tolerated. Importantly, the number of T cells in the tumor microenvironment (TME) has increased. In addition, a patient with metastatic mucosal melanoma did not respond after the previous combined treatment with nivolumab and ipilimumab, but after NT-I7 combined with pembrolizumab, there was a rapid, confirmed partial response, and the tumor was reduced by 46%. RP2D chooses NT-I7 1200 ug/kg IM Q6W + pembro 200 mg IV Q3W combination.
Searching for NeoImmuneTech’s patent layout, NeoImmuneTech also developed a universal CAR-T strategy for NT-I7 combined use. Shows a good combination medication effect.
Moreover, researchers also made related mutants. From the experimental data, the utility of the mutant antibody fusion protein is not as good as WT. As for the future clinical application, it is unknown.
(source:internet, reference only)