Receptor Tyrosine Kinase-like Orphan Receptor Research Articles

Abstract 2941: ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile

Abstract ROR1, a member of the ROR (Receptor Tyrosine Kinase-Like Orphan Receptor)-family, is overexpressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth. The expression is gradually reduced as development progresses, and it is hardly expressed in adults, but the overexpression of ROR1 is observed in various blood and solid cancer cells, so it is classified as an oncofetal gene. ABL102, a First-in-Class bispecific antibody targeting ROR1 and 4-1BB, elicits superior T cell activation by tumor specific T cell engagement through ROR1 dependent 4-1BB clustering. Our data showed that tumor target dependents binding of ROR1 and costimulatory 4-1BB by ABL102 induced 4-1BB activation in cell-based 4-1BB bioassay. ABL102 lead to IFN-γ secretion and tumor cell killing with a ROR1 dependent manner in co-culture assay with tumor cells and human PBMC. In h4-1BB knock-in mouse model bearing hROR1-expressing tumors, ABL102 potently inhibited tumor progression with a high rate of complete remission (CR). Mice with CR were further protected from the rechallenge of previously exposed tumors after 3 months of cessation of ABL102 treatment, implicating that immunological memory might be generated. In 4-week pilot toxicity study using cynomolgus monkeys, no ABL102-related toxicity was observed up to 100mg/kg, including mortality, body weight, hematology, liver toxicity, clinical chemistry and pathology, indicating a favorable safety profile. In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients. Citation Format: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won. ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2941.

Wnt5a might regulate the invasion and proliferation of papillary thyroid carcinoma cells through receptor tyrosine kinase-like orphan receptor 2

Objective To detect the effect of receptor tyrosine kinase-like orphan receptor 2 (ROR2) low-expression combining Wnt5a over-expression on the proliferation and invasion abilities of papillary thyroid carcinoma cells. Methods The proliferation ability of papillary thyroid carcinoma cells with ROR2 low-expressed combining Wnt5a over-expressed was detected by methyl thiazol tetrazolium (MTT). The clone formation ability of papillary thyroid carcinoma cells with ROR2 low-expressed combining Wnt5a over-expressed was detected by colony formation assay. The invasion ability of papillary thyroid carcinoma cells with ROR2 low-expressed combining Wnt5a over-expressed was detected by Transwell. Results MTT assay results showed that the A values detected on the fourth day of the K1 and BCPAP cells of the control groups (0.452±0.005, 0.432±0.003) were significantly lower than those of the Wnt5a groups (0.563±0.004, 0.567±0.006) but higher than those of the Si-ROR2 groups (0.404±0.003, 0.389±0.005) (t=-30.026, -34.857, 14.258, 12.773; P=0.000). The A values detected on the fourth day of the K1 and BCPAP cells of the co-stained groups (0.501±0.005, 0.496±0.003) were distinctively lower than those of the Wnt5a groups (t=-16.771, -19.545; P=0.000). The colony formation assay results showed that the numbers of K1 and BCPAP cell clones of the control groups (101.00±5.43, 112.00±4.11) were distinctively lower than those of the Wnt5a groups (156.00±4.34, 168.00±4.55) but higher than those of the si-ROR2 groups (62.00±4.45, 68.00±3.99) (t=-13.704, -15.819, 9.622, 13.304; P=0.000). The clone numbers of K1 and BCPAP cells of the co-stained groups (121.00±4.44, 128.00±3.89) were significantly lower than those of the Wnt5a groups (t=-9.764, -11.574; P=0.001, 0.000). The Transwell assay demonstrated that the numbers of K1 and BCPAP cells passing through the basement membrane of the control groups [(52.90±2.36), (68.40±1.01) cells] were significantly lower than those of Wnt5a groups [(164.30±4.35), (87.70±1.28) cells] but higher than those of si-ROR2 groups [(31.30±2.17), (39.60±1.34) cells, t=-38.829, -20.502, 11.533, 29.728; P=0.000]. The numbers of K1 and BCPAP cells passing through the basement membrane of the co-stained group [(83.50±1.42), (65.90±2.11) cells] were distinctively lower than those of the Wnt5a groups (t=-31.986, -15.300; P=0.000). Conclusion Wnt5a may regulate the proliferation and invasion of thyroid papillary carcinoma cells through ROR2 signaling. Key words: Wnt5a; Receptor tyrosine kinase-like orphan receptor 2; Papillary thyroid carcinoma; Cell proliferation; Cell invasion