Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Aug;85(3):463–469. doi: 10.1054/bjoc.2000.1940

Chimaeric Lym-1 monoclonal antibody-mediated cytolysis by neutrophils from G-CSF-treated patients: stimulation by GM-CSF and role of Fcγ-receptors

L Ottonello 1, A L Epstein 2, M Mancini 1, G Tortolina 1, P Dapino 1, F Dallegri 1
PMCID: PMC2364058  PMID: 11487281

Abstract

Chimaeric Lym-1 (chLym-1) is a monoclonal antibody generated by fusing the variable region genes of murine Lym-1 to human γ1 and κ constant regions. Owing to its selectivity and avidity for human malignant B cells, it is an attractive candidate for developing immune-interventions in B-lymphomas. In the attempt to identify rational bases for optimizing potential chLym-1 related therapeutic approaches, we studied the ability of this ch-mAb to trigger neutrophil-mediated Raji cell cytolysis in cooperation with two neutrophil-related cytokines, G-CSF and GM-CSF. ChLym-1 triggered low levels of cytolysis by normal neutrophils but induced consistent cytolysis in neutrophils from individuals treated with G-CSF. When exposed to GM-CSF, neutrophils from subjects treated with G-CSF became potent effectors, also leading to 75% lysis. By using mAbs specific for distinct FcγRs, normal neutrophils were inhibited by mAb IV.3, suggesting the intervention of FcγRII, constitutively expressed on the cells. On the other hand, neutrophils from patients treated with G-CSF were inhibited by mAb IV.3 plus mAb 197, a finding consistent with a cooperative intervention of FCγRII and G-CSF-induced FcγRI. The anti-FcγRIII mAb 3G8 promoted significant enhancement of the neutrophil cytolytic efficiency. Therefore, neutrophil FcγRIII behaves as a down-regulator of the cytolytic potential. The present findings suggest new attempts to develop mAb-based and G-CSF/GM-CSF combined immune-interventions in B lymphomas. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: neutrophils; ADCC; chLym-1; FcγR, lymphoma

Full Text

The Full Text of this article is available as a PDF (88.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Biddle W. C., Pancook J., Goldrosen M., Han T., Foon K. A., Vaickus L. Antibody-dependent, cell-mediated cytotoxicity by an anti-class II murine monoclonal antibody: effects of recombinant interleukin 2 on human effector cell lysis of human B-cell tumors. Cancer Res. 1990 May 15;50(10):2991–2996. [PubMed] [Google Scholar]
  2. Blackhall F. H., Ranson M., Radford J. A., Hancock B. W., Soukop M., McGown A. T., Robbins A., Halbert G., Jayson G. C., Cancer Research Campaign Phase I/II Committee A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma. Br J Cancer. 2001 Feb;84(4):465–469. doi: 10.1054/bjoc.2000.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blackhall F. H., Ranson M., Radford J. A., Hancock B. W., Soukop M., McGown A. T., Robbins A., Halbert G., Jayson G. C., Cancer Research Campaign Phase I/II Committee A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma. Br J Cancer. 2001 Feb;84(4):465–469. doi: 10.1054/bjoc.2000.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. DeNardo G. L., Lamborn K. R., Goldstein D. S., Kroger L. A., DeNardo S. J. Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Cancer. 1997 Dec 15;80(12 Suppl):2706–2711. doi: 10.1002/(sici)1097-0142(19971215)80:12+<2706::aid-cncr49>3.3.co;2-m. [DOI] [PubMed] [Google Scholar]
  5. Elsässer D., Valerius T., Repp R., Weiner G. J., Deo Y., Kalden J. R., van de Winkel J. G., Stevenson G. T., Glennie M. J., Gramatzki M. HLA class II as potential target antigen on malignant B cells for therapy with bispecific antibodies in combination with granulocyte colony-stimulating factor. Blood. 1996 May 1;87(9):3803–3812. [PubMed] [Google Scholar]
  6. Epstein A. L., Marder R. J., Winter J. N., Stathopoulos E., Chen F. M., Parker J. W., Taylor C. R. Two new monoclonal antibodies, Lym-1 and Lym-2, reactive with human B-lymphocytes and derived tumors, with immunodiagnostic and immunotherapeutic potential. Cancer Res. 1987 Feb 1;47(3):830–840. [PubMed] [Google Scholar]
  7. Gavioli R., Spisani S., Giuliani A. L., Cosulich E., Risso A., Traniello S. CD16 and CR3 receptors distinguish between the two mechanisms of tumour cytotoxicity in neutrophils. Br J Haematol. 1991 Oct;79(2):170–176. doi: 10.1111/j.1365-2141.1991.tb04518.x. [DOI] [PubMed] [Google Scholar]
  8. Gessner J. E., Heiken H., Tamm A., Schmidt R. E. The IgG Fc receptor family. Ann Hematol. 1998 Jun;76(6):231–248. doi: 10.1007/s002770050396. [DOI] [PubMed] [Google Scholar]
  9. Graziano R. F., Fanger M. W. Fc gamma RI and Fc gamma RII on monocytes and granulocytes are cytotoxic trigger molecules for tumor cells. J Immunol. 1987 Nov 15;139(10):3536–3541. [PubMed] [Google Scholar]
  10. Hu E., Epstein A. L., Naeve G. S., Gill I., Martin S., Sherrod A., Nichols P., Chen D., Mazumder A., Levine A. M. A phase 1a clinical trial of LYM-1 monoclonal antibody serotherapy in patients with refractory B cell malignancies. Hematol Oncol. 1989 Mar-Apr;7(2):155–166. doi: 10.1002/hon.2900070207. [DOI] [PubMed] [Google Scholar]
  11. Hu P., Glasky M. S., Yun A., Alauddin M. M., Hornick J. L., Khawli L. A., Epstein A. L. A human-mouse chimeric Lym-1 monoclonal antibody with specificity for human lymphomas expressed in a baculovirus system. Hum Antibodies Hybridomas. 1995;6(2):57–67. [PubMed] [Google Scholar]
  12. Huizinga T. W., de Haas M., Kleijer M., Nuijens J. H., Roos D., von dem Borne A. E. Soluble Fc gamma receptor III in human plasma originates from release by neutrophils. J Clin Invest. 1990 Aug;86(2):416–423. doi: 10.1172/JCI114727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kerst J. M., de Haas M., van der Schoot C. E., Slaper-Cortenbach I. C., Kleijer M., von dem Borne A. E., van Oers R. H. Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells. Blood. 1993 Dec 1;82(11):3265–3272. [PubMed] [Google Scholar]
  14. Kushner B. H., Cheung N. K. Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. Blood. 1992 Mar 15;79(6):1484–1490. [PubMed] [Google Scholar]
  15. Kushner B. H., Cheung N. K. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood. 1989 May 15;73(7):1936–1941. [PubMed] [Google Scholar]
  16. Michon J. M., Gey A., Moutel S., Tartour E., Meresse V., Fridman W., Teillaud J. L. In vivo induction of functional Fc gammaRI (CD64) on neutrophils and modulation of blood cytokine mRNA levels in cancer patients treated with G-CSF (rMetHuG-CSF). Br J Haematol. 1998 Mar;100(3):550–556. doi: 10.1046/j.1365-2141.1998.00597.x. [DOI] [PubMed] [Google Scholar]
  17. Ottonello L., Epstein A. L., Dapino P., Barbera P., Morone P., Dallegri F. Monoclonal Lym-1 antibody-dependent cytolysis by neutrophils exposed to granulocyte-macrophage colony-stimulating factor: intervention of FcgammaRII (CD32), CD11b-CD18 integrins, and CD66b glycoproteins. Blood. 1999 May 15;93(10):3505–3511. [PubMed] [Google Scholar]
  18. Ottonello L., Morone P., Dapino P., Dallegri F. Monoclonal Lym-1 antibody-dependent lysis of B-lymphoblastoid tumor targets by human complement and cytokinine-exposed mononuclear and neutrophilic polymorphonuclear leukocytes. Blood. 1996 Jun 15;87(12):5171–5178. [PubMed] [Google Scholar]
  19. Porter J. C., Hogg N. Integrins take partners: cross-talk between integrins and other membrane receptors. Trends Cell Biol. 1998 Oct;8(10):390–396. doi: 10.1016/s0962-8924(98)01344-0. [DOI] [PubMed] [Google Scholar]
  20. Repp R., Valerius T., Sendler A., Gramatzki M., Iro H., Kalden J. R., Platzer E. Neutrophils express the high affinity receptor for IgG (Fc gamma RI, CD64) after in vivo application of recombinant human granulocyte colony-stimulating factor. Blood. 1991 Aug 15;78(4):885–889. [PubMed] [Google Scholar]
  21. Rose L. M., Gunasekera A. H., DeNardo S. J., DeNardo G. L., Meares C. F. Lymphoma-selective antibody Lym-1 recognizes a discontinuous epitope on the light chain of HLA-DR10. Cancer Immunol Immunother. 1996 Sep;43(1):26–30. doi: 10.1007/s002620050299. [DOI] [PubMed] [Google Scholar]
  22. Todd R. F., 3rd, Petty H. R. Beta 2 (CD11/CD18) integrins can serve as signaling partners for other leukocyte receptors. J Lab Clin Med. 1997 May;129(5):492–498. doi: 10.1016/s0022-2143(97)90003-2. [DOI] [PubMed] [Google Scholar]
  23. Unkeless J. C. Function and heterogeneity of human Fc receptors for immunoglobulin G. J Clin Invest. 1989 Feb;83(2):355–361. doi: 10.1172/JCI113891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Vaickus L., Biddle W., Cemerlić D., Foon K. A. Interferon gamma augments Lym-1-dependent, granulocyte-mediated tumor cell lysis. Blood. 1990 Jun 15;75(12):2408–2416. [PubMed] [Google Scholar]
  25. Valerius T., Elsässer D., Repp R., Van de Winkel J. G., Gramatzki M., Glennie M. HLA class II antibodies recruit G-CSF activated neutrophils for treatment of B cell malignancies. Leuk Lymphoma. 1997 Jul;26(3-4):261–269. doi: 10.3109/10428199709051775. [DOI] [PubMed] [Google Scholar]
  26. Valerius T., Repp R., de Wit T. P., Berthold S., Platzer E., Kalden J. R., Gramatzki M., van de Winkel J. G. Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy. Blood. 1993 Aug 1;82(3):931–939. [PubMed] [Google Scholar]
  27. Würflein D., Dechant M., Stockmeyer B., Tutt A. L., Hu P., Repp R., Kalden J. R., van de Winkel J. G., Epstein A. L., Valerius T. Evaluating antibodies for their capacity to induce cell-mediated lysis of malignant B cells. Cancer Res. 1998 Jul 15;58(14):3051–3058. [PubMed] [Google Scholar]
  28. Zhou M. J., Brown E. J. CR3 (Mac-1, alpha M beta 2, CD11b/CD18) and Fc gamma RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc gamma RIII and tyrosine phosphorylation. J Cell Biol. 1994 Jun;125(6):1407–1416. doi: 10.1083/jcb.125.6.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES