750 AK119, a CD73 targeting antibody with dual mechanism of action

Background AK119 is an Fc-engineered humanized IgG1 monoclonal antibody targeting human CD73. CD73-extracellular adenosine pathway regulates conversion of pro-inflammatory and immuno-stimulatory extracellular ATP into immunosuppressive adenosine. CD73 expresses on cancer cells, endothelial fibroblasts, lymphocytes myeloid cells. upregulated can be a result tissue hypoxia, 1 epithelial-to-mesenchymal transition, 2 inflammation 3 and/or cytotoxic stress. 4 Also, increasing immune response may lead to faster viral clearance, shorter recovery time, less complications, longer immunity protection from re-infection. Inhibiting was reported evoke B cells activation shows anti-fibrotic effects. The ability enhancing provides potential opportunity treat COVID-19. Thus, we investigated pharmacological activity as agent treating cancers, COVID-19 fibrosis. Methods inhibition enzymatic tested in PBMCs based assay. enhance detected by cell-based were incubated overnight with APCP (inhibitor enzyme acitvity) or AK119, CPI006 MEDI9447. Flow cytometry analysis performed gating (CD19+CD3-) MFI positive percent for staining CD69 CD83, well HLA-DR IgM. Enhancement anti-SARS-CoV-2 production studied using transgenic mouse immunized SARS-CoV-2 spike protein. in-vivo further bleomycin-induced pulmonary fibrosis model mouse. Results more potent antigen binding (figure 1) completely 2). promotes cell proliferation, upregulating CD69, IgM that are markers 3). induced independent show significantly higher bioactivity induce comparison MEDI9447 4). In mice, increased secretion anti-S protein IgG 5). model, number inflammatory broncholveolr lavage fluid decreased, decreased HYP representing collagen content lung homogenate mice found both 50 mg/kg 10 group 6). Conclusions selectively binds inhibits the ectonucleotidase thus reducing accumulation. non-clinical pharmacology studies reveal bioactivities favorable safety properties AK119. intended advanced solid tumors, therapy References Bullen JW, Tchernyshyov I, Holewinski RJ, DeVine L, Wu F, Venkatraman V, Kass DL, Cole RN, Van Eyk J, Semenza GL, Protein kinase A-dependent phosphorylation stimulates transcriptional hypoxia-inducible factor 1. Sci Signal 2016; 9 (430):ra56. Lupia M, Angiolini Bertalot G, Freddi S, Sachsenmeier KF, Chisci E, Kutryb-Zajac B, Confalonieri Smolenski RT, Giovannoni R, Colombo N, Bianchi Cavallaro U. stemness epithelial-Mesenchymal transition ovarian cancer-initiating Stem Cell Rep 2018; (4):1412–1425. Reinhardt Landsberg Schmid-Burgk JL, Ramis BB, Bald T, Glodde Lopez-Ramos D, Young A, Ngiow SF, Nettersheim Schorle H, Quast Kolanus W, Schadendorf Long GV, Madore Scolyer RA, Ribas Smyth MJ, Tumeh PC, Tuting Holzel M. MAPK signaling link melanoma phenotype switching induction during immunotherapy. Cancer Res 2017;77(17):4697–4709. Samanta Park Y, Ni X, Li Zahnow CA, Gabrielson Pan GL. Chemotherapy induces enrichment CD47(+)/CD73(+)/ PDL1(+) evasive triple-negative breast Proc Natl Acad USA. 115 (6):E1239–E1248. Abstract 750 Figure Binding PBMCs. Curve expressed (A) CD8+ T (B) CD19+ Inhibition Inhibits Enzymatic Activity Expressed Effect Upregulates (C) (D) Expression Stimulation Proliferation 5 Therapeutic model. Serum Concentration S protein-specific Mouse Model 6 asthma relieves airway resistance restore function. Reduction BALF