Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 Jul;36(4):267–273. doi: 10.1007/BF01740909

Phase I trial of chimeric (human-mouse) monoclonal antibody L6 in patients with non-small-cell lung, colon, and breast cancer

Gary E Goodman 1, Ingegerd Hellstrom 2, Dale E Yelton 2, James L Murray 3, Sarah O'Hara 1, Elaine Meaker 2, Lane Zeigler 3, Paulette Palazollo 3, Claude Nicaise 2, J Usakewicz, Karl Erik Hellstrom 2
PMCID: PMC11038372  PMID: 8382560

Abstract

We report a single institution phase I trial of chimeric (mouse-human) monoclonal antibody (chL6) directed against a tumor-associated cell surface antigen expressed in non-small cell lung, colon, and breast cancer. The results of the study were contrasted with a previous trial of murine L6. ChL6 was administered intravenously to 18 patients with advanced cancer as a single, 4–16 infusion in doses ranging from 350 mg/m2 to 700 mg/m2. One patient received four weekly doses of 350 mg/m2. Patients were followed for side effects, localization of antibody to tumor cells, pharmacokinetics and the development of antibodies against chL6. Side effects associated with treatment were chills, fever, and nausea, which lasted 24–48 hours. Platelet count and absolute leukocyte count fell immediately after treatment, but returned to pretreatment levels by day 7. Localization of chL6 to tumor cells in vivo was seen at 350 mg/m2 and “saturation” at 700 mg/m2 and 350 mg/m2 per week×4. The pharmacokinetics of this antibody appeared similar to its murine analogue. Human antibodies against chL6 were detected in only 4 of 18 patients. These antibodies were directed against murine variable regent and their titers were lower than those occurring in most patients who received murine L6 in an earlier trial. No tumor reductions were seen. Chimeric L6 appears to be a suitable antibody for delivering anti-tumor agents because of its low immunogenicity and favorable in vivo tumor binding characteristics.

Key words: Chimeric, Monoclonal antibody, Phase I trial, Non-small-cell lung cancer, Colon cancer, Breast cancer

References

  • 1.Bajorin DF, Chapman PB, Wong G, Coi DG, Kunicka J, Dimaggio J, Cordon-Cardo C, Urmacher C, Dantes L, Templeton MA, Liu J, Oettgen HF, Houghton AN. Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma. Cancer Res. 1990;50:7490–7495. [PubMed] [Google Scholar]
  • 2.DeNardo SJ, O'Grady LF, Macey DJ, Kroger LA, McNardo GL, Lamborn KR, Levy NB, Mills SL, Hellstrom I, Hellstrom KE. Quantitative imaging of mouse L6 monoclonal antibody in breast cancer patients to develop a therapeutic strategy. Nucl Med Biol. 1991;18:621–631. doi: 10.1016/0883-2897(91)90032-g. [DOI] [PubMed] [Google Scholar]
  • 3.DeNardo SJ, Warhoe KA, O'Grady LF, Hellstrom I, Hellstrom KE, Mills SL, Macey DJ, Goodnight JE, DeNardo GL. Radioimmunotherapy for breast cancer: treatment of a patient with I-131 LG chimetric monoclonal antibody. Int J Biol Markers. 1991;6:221–230. doi: 10.1177/172460089100600402. [DOI] [PubMed] [Google Scholar]
  • 4.Epenetos AA, Kosmas C. Monoclonal antibodies for imaging and therapy. Br J Cancer. 1989;59:152–152. doi: 10.1038/bjc.1989.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Fell HP, Gayle MA, Schieven G, Yelton D, Lipsich L, Hellstrom I, Hellstrom KE, Bajorath J (1992) Chimeric L6 anti-tumor antibody: genomic construction, variable region gone sequencing, and binding site modeling. J Biol Chem (in press) [PubMed]
  • 6.Garrigues HJ, Tilgen W, Hellstrom I, Franke W, Hellstrom KE. Detection of a human melanoma-associated antigen, p97, in histological sections of primary human melanomas. Int J Cancer. 1982;29:511–515. doi: 10.1002/ijc.2910290505. [DOI] [PubMed] [Google Scholar]
  • 7.Goodman GE, Beaumier PL, Hellstrom I, Fernyhough B, Hellstrom KE. Pilot trial of murine monoclonal antibodies in patients with advanced melanoma. J Clin Oncol. 1985;3:340–340. doi: 10.1200/JCO.1985.3.3.340. [DOI] [PubMed] [Google Scholar]
  • 8.Goodman GE, Hellstrom I, Brodzinsky L, Nicaise C, Kulander B, Hummel D, Hellstrom KE. Phase I trial of murine monoclonal antibody L6 in breast, colon, ovarian, and lung cancer. J Clin Oncol. 1990;8:1083–1092. doi: 10.1200/JCO.1990.8.6.1083. [DOI] [PubMed] [Google Scholar]
  • 9.Hank JA, Robinson RR, Sufus J, Mueller BM, Reisfeld RA, Cheung NK, Sondel PM. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. Cancer Res. 1990;50:5234–5239. [PubMed] [Google Scholar]
  • 10.Hellstrom KE, Hellstrom I. Principles of tumor immunity: tumor antigens. In: DeVita VT, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer: principles and practice. Philadelphia: Lippincott; 1991. pp. 35–52. [Google Scholar]
  • 11.Hellstrom I, Beaumier PL, Hellstrom KE. Antitumor effects of L6, an IgG2a antibody reacting with most human carcinomas. Proc Natl Acad Sci USA. 1986;83:7059–7059. doi: 10.1073/pnas.83.18.7059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Hellstrom I, Garrigues U, Lavie E, Hellstrom KE. Antibodymediated killing of human tumor cells by attached effector cells. Cancer Res. 1988;48:624–627. [PubMed] [Google Scholar]
  • 13.Koprowski H, Herlyn D, Lubeck M, DeFreitas E, Scars HF. Human anti-idiotype antibodies in cancer patients: is the modulation of the immune response beneficial for the patient. Proc Natl Acad Sci USA. 1984;81:216–219. doi: 10.1073/pnas.81.1.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Liu AY, Robinson RR, Hellstrom KE, Murray ED, Jr, Chang CP, Hellstrom I. Chimeric mouse-human IgG1 antibody that can mediate lysis of cancer cells. Proc Natl Acad Sci USA. 1987;84:3439–3443. doi: 10.1073/pnas.84.10.3439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Marken JS, Schieven GL, Hellstrom I, Hellstrom KE, Aruffo A. Cloning and expression of the tumor-associated antigen L6. Proc Natl Acad Sci USA. 1992;89:3503–3507. doi: 10.1073/pnas.89.8.3503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Schultz KR, Klarnet JP, Peace DJ, Cheever MA, Badger CC, Bernstein ID, Greenberg PD. Monoclonal antibody therapy of murine lymphoma: Enhanced efficacy by concurrent administration of interleukin 2 or lymphokine-activated killer cells. Cancer Res. 1990;50:5421–5425. [PubMed] [Google Scholar]
  • 17.Shaw DR, Khazaeli MB, LoBuglio AF. Biologic activity of mouse/human chimeric antibodies of the human IgG subclasses with specificity for a tumor associated antigen. Proc Natl Acad Sci USA. 1989;86:4220–4224. [Google Scholar]
  • 18.Sternberger LA. The unlabeled antibody peroxidase-antiperoxidase (PAP) method. In: Sternberger LA, editor. Immunocytochemistry. New York: Wiley; 1979. pp. 104–169. [Google Scholar]
  • 19.Vadhan-Raj S, Cordon-Cardo C, Carswell E, Mintzer D, Dantis L, Duteau C, Templeton MA, Dettgen HF, Old LJ, Houghton AN. Phase I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites. J Clin Oncol. 1988;6:1636–1648. doi: 10.1200/JCO.1988.6.10.1636. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES