781 GT-001 - anti-Lewis Y antibody with superior fine-specificity and reduced off-target binding

Background The Lewis Y (CD174) carbohydrate antigen is widely expressed in primary and metastatic epithelial tumors like colon, lung, ovarian, breast. Targeting for cancer therapy was pursued before, however, other anti-Lewis antibodies tested clinical trials showed cross-reactivity to related structures on blood cells mostly failed efficacy and/or safety reasons. 1–4 We have developed a humanized antibody (GT-001) that shows superior fine-specificity higher affinity compared clinically BR96 h3S193. Methods specificity of GT-001, h3S193 were compared. Cross-reactivity binding PAA-conjugates via ELISA towards Y-PAA measured using switchSENSE ® technology (DRX2, Dynamic Biosensors). Functional several tumor cell lines healthy human leukocytes analyzed flow cytometry. Binding GT-001 different indications by immunohistochemistry. Inhibition proliferation coupled ProtG-MMAE. Results strictly specific does not cross-react with >90 tested. Our lead candidate BR96, which we could confirm the reported X, 5 stronger as shown measurement. Further, no/weak whereas significantly bind leukocyte subsets. IHC studies reveal stains tissue (breast cancer, colorectal head neck (non) small lung ovarian cancer) at high percentage cases. In ADC surrogate assays, potently inhibits indicating effective internalization. Conclusions many medical need. However, approaches targeting past Due fine-specificity, no/reduced potentially reducing side effects observed clinic. Its strong target internalization properties make an ideal development. References Ajani JA, Kelsen DP, Haller D, Hargraves K, Healey D. A multi-institutional phase II study BMS-182248-01 (BR96-doxorubicin conjugate) administered every 21 days patients advanced gastric adenocarcinoma. Cancer J 2000; 6 (2):78–81. Saleh MN, Sugarman S, Murray J, Ostroff JB, Jones Daniel CR, LeBherz Brewer H, Onetto N, LoBuglio AF. Phase I trial drug immunoconjugate BR96-doxorubicin lewis Y-expressing tumors. Clin Oncol 18 (11):2282–92. Scott AM, Tebbutt Lee FT, Cavicchiolo T, Liu Z, Gill Poon Hopkins W, Smyth FE, Murone C, MacGregor Papenfuss AT, Chappell B, Saunder TH, Brechbiel MW, Davis ID, Murphy R, Chong G, Hoffman EW, Old LJ. biodistribution pharmacokinetic monoclonal Hu3s193 cancers express Lewis-Y antigen. Res 2007; 13 (11):3286–92. Smaletz O, Diz MD, do Carmo CC, Sabbaga Cunha-Junior GF, Azevedo SJ, Maluf FC, Barrios CH, Costa RL, Fontana AG, Madrigal V, Wainstein AJ, Yeda FP, Alves VA, Moro Blasbalg EW. anti-Lewis-Y (hu3S193) treatment platinum resistant/refractory fallopian tube peritoneal carcinoma. Gynecol 2015; 138 (2):272–7. Zhang HS, Cordon-Cardo Reuter VE, Singhal AK, Lloyd KO, Livingston PO. Selection antigens targets immune attack immunohistochemistry: II. Blood group-related antigens. Int 1997; 73 (1):50–6.