Targeting Lewis Y (Le(y)) in small cell lung cancer with a humanized monoclonal antibody, hu3S193: a pilot trial testing two dose levels.
BACKGROUND
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.
Krug
Lee M
LM
Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College at Cornell University, New York, NY 10021, USA. krugl@mskcc.org
Milton
Daniel T
DT
Jungbluth
Achim A
AA
Chen
Lin-Chi
LC
Quaia
Emilio
E
Pandit-Taskar
Neeta
N
Nagel
Andrew
A
Jones
Jessica
J
Kris
Mark G
MG
Finn
Ronald
R
Smith-Jones
Peter
P
Scott
Andrew M
AM
Old
Lloyd
L
Divgi
Chaitanya
C
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001859:Bone Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D001932:Brain Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007983:Lewis Blood Group Antigens / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C522039:Hu3S193 monoclonal antibody; D007205:Indium Radioisotopes; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen