Discovery and Optimization of HKT288, a Cadherin-6 Targeting ADC for the Treatment of Ovarian and Renal Cancer.
(1) Bialucha CU (2) Collins SD (3) Li X (4) Saxena P (5) Zhang X (6) Durr C (7) LaFont B (8) Prieur P (9) Shim Y (10) Mosher R (11) Lee D (12) Ostrom L (13) Hu T (14) Bilic S (15) Liric Rajlic I (16) Capka V (17) Jiang W (18) Wagner JP (19) Elliott G (20) Veloso A (21) Piel JC (22) Flaherty MM (23) Mansfield KG (24) Meseck EK (25) Rubic-Schneider T (26) Serdakowski London A (27) Tschantz WR (28) Kurz M (29) Nguyen D (30) Bourret A (31) Meyer MJ (32) Faris JE (33) Janatpour MJ (34) Chan VW (35) Yoder NC (36) Catcott KC (37) McShea MA (38) Sun X (39) Gao H (40) Williams J (41) Hofmann F (42) Engelman JA (43) Ettenberg SA (44) Sellers WR (45) Lees E
(1) Bialucha CU (2) Collins SD (3) Li X (4) Saxena P (5) Zhang X (6) Durr C (7) LaFont B (8) Prieur P (9) Shim Y (10) Mosher R (11) Lee D (12) Ostrom L (13) Hu T (14) Bilic S (15) Liric Rajlic I (16) Capka V (17) Jiang W (18) Wagner JP (19) Elliott G (20) Veloso A (21) Piel JC (22) Flaherty MM (23) Mansfield KG (24) Meseck EK (25) Rubic-Schneider T (26) Serdakowski London A (27) Tschantz WR (28) Kurz M (29) Nguyen D (30) Bourret A (31) Meyer MJ (32) Faris JE (33) Janatpour MJ (34) Chan VW (35) Yoder NC (36) Catcott KC (37) McShea MA (38) Sun X (39) Gao H (40) Williams J (41) Hofmann F (42) Engelman JA (43) Ettenberg SA (44) Sellers WR (45) Lees E
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development. In order to more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models - a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT and features a pre-clinical safety profile supportive of progression towards clinical evaluation.
Author Info:
(1) Oncology, Novartis Institutes for Biomedical Research carl_uli.bialucha@novartis.com. (2) Oncology, Novartis Institutes for Biomedical Research. (3) Oncology, Novartis Institut
es for Biomedical Research. (4) Oncology, Novartis Institutes for Biomedical Research. (5) Oncology, Novartis Institutes for BioMedical Research. (6) Novartis Institutes for Biomedical Research. (7) Novartis Institutes for Biomedical Research. (8) Novartis Institutes for Biomedical Research. (9) Oncology Translational Research, Novartis Institutes for BioMedical Research. (10) Novartis Institutes for Biomedical Research. (11) Novartis Institutes for Biomedical Research. (12) Novartis Institutes for Biomedical Research. (13) Center Proteomic Chemistry, Novartis Institutes for Biomedical Research. (14) Novartis Institutes for Biomedical Research. (15) Novartis Institutes for Biomedical Research. (16) Novartis Institutes for Biomedical Research. (17) Novartis Institutes for Biomedical Research. (18) Oncology, Novartis Institutes for Biomedical Research. (19) Oncology, Novartis Institutes for Biomedical Research. (20) Novartis Institutes for Biomedical Research. (21) Novartis Institutes for Biomedical Research. (22) Novartis Institutes for Biomedical Research. (23) Preclinical Safety, Novartis Institutes for Biomedical Research. (24) Novartis Institutes for Biomedical Research. (25) Novartis Institutes for Biomedical Research. (26) NBC, Novartis Institutes for Biomedical Research. (27) Novartis Biologics Center, Novartis Institutes for Biomedical Research. (28) Novartis Institutes for Biomedical Research. (29) Novartis Institutes for Biomedical Research. (30) Novartis Institutes for Biomedical Research. (31) Oncology Research, Novartis Institutes for Biomedical Research. (32) Department of Medicine, Massachusetts General Hospital. (33) Novartis Institutes for Biomedical Research. (34) Portfolio Management, Eureka Therapeutics. (35) ImmunoGen Inc. (36) Biochemistry, ImmunoGen Inc. (37) ImmunoGen Inc. (38) ImmunoGen Inc. (39) Oncology, Novartis Institutes for Biomedical Research. (40) Disease Area Oncology, Novartis Institutes for Biomedical Research. (41) Oncology Disease Area, Novartis Institutes for Biomedical Research. (42) Novartis Institutes for Biomedical Research. (43) Oncology, Novartis Institutes for Biomedical Research. (44) Novartis Institutes for Biomedical Research. (45) Novartis Institutes for Biomedical Research.
Citation: Cancer Discov 2017 May 19 Epub05/19/2017
