Cutaneous T cell lymphoma (CTCL) is a type of non-Hodgkin's lymphoma in which malignant T cells initially home to the skin followed by systemic dissemination as the disease progresses. CD70 is rarely expressed in normal tissues but is overexpressed in activated T and B lymphocytes. From archival diagnostic specimens of 37 patients, we demonstrate that CD70 is highly expressed in subtypes of mature TCL, especially CTCL. SGNCD70A is a new anti-CD70 antibody-drug conjugate combining a monoclonal antibody to CD70 with a DNA-damaging agent. SGNCD70A inhibited cell growth and induced apoptosis of CD70+ CTCL cell lines and primary tumors from patient-derived xenograft (PDX) mice, but had no inhibitory effect on CD70- lymphoblastic TCL cells and normal T cells. Next, we examined the anti-tumor activity of SGNCD70A in CTCL PDX model. One week after tumor inoculation, mice were treated intraperitoneally with single-dosing of PBS, 100 μg/kg (SGN70A100) or 300 μg/kg (SGN70A300) of SGN-CD70A. SGN-CD70A prolonged survival of treated mice in a dose-dependent fashion compared to untreated mice. Median survival was 21 days, 27.5 days (P=0.041), and 57 days (p<0.01) for the PBS control, SGN70A100 and SGN70A300 group, respectively. To confirm that survival was dictated by disease progression, rather than drug toxicity of SGN-CD70A, we measured tumor burden by cell-free DNA (cfDNA) throughout the course of treatment. We demonstrated that cfDNA paralleled the disease progression and peaked before death of the animals. In contrast, in surviving mice, cfDNA remained at the background level. Importantly, we discovered relapse occurred in SGN70A300 group (3 of 4, 75%) due to persistent disease, not due to acquired resistance to SGN-CD70A. Thus, we investigated whether multiple dosing could lead to complete regression of tumors in PDX model. We treated PDX mice with SGN70A300 weekly (SGN70A300x3) for 3 consecutive weeks. In the SGN70A300x3 group, three of four mice survived beyond day 90 (median >85 days), resulting in markedly prolonged survival compared to the single-dose- and PBS-treated mice with a median survival of 39 days, (P<0.01) and 20 days (P<0.01), respectively. Compared to PBS group, both SGN70A300 and SGN70A300x3 treated mice had delayed tumor growth and cfDNA rise. Furthermore, in SGN70A300 group, cfDNA started to rise seven days before the endpoint of the mice in a range of 30-42 days, while three surviving mice in SGN70A300x3 remained at background cfDNA levels until day 85, indicating that multiple doses of SGN-CD70A decreased overall tumor burden and the occurrence of relapse in CTCL. Our results showed that CD70 is highly expressed in mature TCL, especially in CTCL. Using CTCL PDX models, SGN-CD70A has marked anti-tumor activity, leading to long-term survival of treated mice. Our results provide a rationale for clinical investigation of SGN-CD70A in patients with TCL.

Citation Format: Chi-Heng Wu, Chen-Yen Yang, Linlin Wang, Ryan Gill, Frank McCormick, Weiyun Z. Ai. A CD70 antibody-drug conjugate is highly active and induces long term remission in patient-derived xenograft mouse models of cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1844.