Targeting Lewis Y (LeY) in small cell lung cancer (SCLC) with a humanized monoclonal antibody, hu3S193

Abstract

7086 Background: LeY is a blood group antigen with dominant expression on the surface of epithelial tumors, including SCLC, making it a potential target for antibody-based immunotherapy. 3S193, an IgG3 mAb, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-LeY antibodies. A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m2 demonstrated tumor targeting without serious toxicities or the development of human antihuman antibodies (Scott et al, ASCO, 2004). Methods: We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three prior chemotherapy regimens, measurable disease not previously irradiated, and tumor samples immunohistochemistry (IHC)-positive for 3S193. Patients received four weekly injections of hu3S193, 5 patients at 10mg/m2 and 5 patients at 20 mg/m2. The first and fourth injections were radiolabeled with 111Indium for gamma camera imaging. Results: Of 40 patients screened, 25/34 (74%) evaluable SCLC tumor samples were 3S193-positive by IHC: 1+ (n = 13), 2+ (n = 3), 3+ (n = 2), 4+ (n = 7). Ten patients were treated with hu3S193; eight completed all four injections (one had disease progression and one is still on treatment). At the lower dose, about 50% of lesions >2 cm diameter visualized on FDG-PET were also seen on 111In SPECT imaging. However, at the higher dose, essentially all FDG avid lesions showed targeting. The mean T1/2 for all infusions was 2.89 ± 0.84 days at 10 mg/m2 (n = 9) and 3.29 ± 0.66 days at 20 mg/m2 (n = 7). No difference was noted in imaging or pharmacokinetics between the first and fourth injections. At the 20 mg/m2 dose, patients experienced grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion. No other grade 2 or greater toxicities were observed. No objective responses were observed. Conclusions: SCLC has a high rate of Lewis Y expression. Given the strong tumor targeting, particularly at the higher dose, and the potential for immunomodulatory effects, administration of hu3S193 with chemotherapy would be warranted. Supported by the Ludwig Institute and the Experimental Therapeutics Committee of MSKCC. No significant financial relationships to disclose.