Targeting Lewis Y (Le(y)) in small cell lung cancer with a humanized monoclonal antibody, hu3S193: a pilot trial testing two dose levels

Lee M Krug, Daniel T Milton, Achim A Jungbluth, Lin-Chi Chen, Emilio Quaia, Neeta Pandit-Taskar, Andrew Nagel, Jessica Jones, Mark G Kris, Ronald Finn, Peter Smith-Jones, Andrew M Scott, Lloyd Old, Chaitanya Divgi

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Lewis Y (Le(y)) is a blood group antigen with robust expression on the surface of epithelial tumors, including small cell lung cancer (SCLC), making it a potential target for antibody-based immunotherapy. 3S193, an immunoglobulin G3 monoclonal antibody, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-Le(y) 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 anti-human antibodies.

METHODS: We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three previous chemotherapy regimens, measurable disease not previously irradiated, and tumor samples positive for 3S193 by immunohistochemistry. Patients received four weekly injections of hu3S193, five patients at 10 mg/m2 and five patients at 20 mg/m2. The first and fourth injections were radiolabeled with indium-111 for gamma camera imaging.

RESULTS: Of 40 patients screened, 25 of 34 (74%) assessable SCLC tumor samples were 3S193 positive by immunohistochemistry. Ten patients were treated with hu3S193; nine completed all four injections. All fluorodeoxyglucose (FDG)-avid lesions >2 cm were visualized on antibody single-photon emission computed tomography. Some lesions overlying vascular structures could not be visualized. No difference was noted in imaging or pharmacokinetics between the first and fourth injections. Toxicities included grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion at the higher dose.

CONCLUSIONS: Given the strong tumor targeting, particularly at the higher dose, the favorable toxicity profile, and the potential for immunomodulatory effects, hu3S193 warrants further investigation in SCLC.

Original languageEnglish
Pages (from-to)947-52
Number of pages6
JournalJournal of Thoracic Oncology
Volume2
Issue number10
DOIs
Publication statusPublished - Oct 2007

Keywords

  • Adult
  • Aged
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Bone Neoplasms
  • Brain Neoplasms
  • Carcinoma, Small Cell
  • Female
  • Humans
  • Indium Radioisotopes
  • Lewis Blood-Group System
  • Liver Neoplasms
  • Lung Neoplasms
  • Male
  • Middle Aged
  • Pilot Projects
  • Radioimmunotherapy
  • Time Factors
  • Tissue Distribution
  • Treatment Outcome

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