Harnessing engineered antibodies of the IgE class to combat malignancy: Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity

S. M. Rudman, D. H. Josephs, H. Cambrook, P. Karagiannis, A. E. Gilbert, T. Dodev, J. Hunt, A. Koers, A. Montes, L. Taams, S. Canevari, M. Figini, P. J. Blower, A. J. Beavil, C. F. Nicodemus, C. Corrigan, S. B. Kaye, F. O. Nestle, H. J. Gould, J. F. SpicerS. N. Karagiannis

Research output: Contribution to journalArticle

Abstract

Background IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, Fce{open}RI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-Fce{open}RI complexes on basophils to cause type I hypersensitivity. Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fce{open}RI-mediated type I hypersensitivity. Methods As validated readouts of the potential for MOv18 to cause Fce{open}RI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) Fce{open}RI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. Results Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fce{open}RI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

Original languageEnglish
Pages (from-to)1400-1413
Number of pages14
JournalClinical and Experimental Allergy
Volume41
Issue number10
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Immediate Hypersensitivity
Basophils
Immunoglobulin Isotypes
Folic Acid
Immunoglobulin E
Antibodies
IgE Receptors
Neoplasms
Ovarian Neoplasms
Carcinoma
Healthy Volunteers
Cell Degranulation
Antigen Receptors
Serum
Eosinophils
Heterografts
Mast Cells
Epitopes
Leukemia
Immunoglobulin G

Keywords

  • Anaphylaxis
  • Basophil
  • Cancer therapy
  • CD63
  • Degranulation
  • FRα
  • Tumour antigen-specific IgE
  • Type I hypersensitivity

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Harnessing engineered antibodies of the IgE class to combat malignancy : Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity. / Rudman, S. M.; Josephs, D. H.; Cambrook, H.; Karagiannis, P.; Gilbert, A. E.; Dodev, T.; Hunt, J.; Koers, A.; Montes, A.; Taams, L.; Canevari, S.; Figini, M.; Blower, P. J.; Beavil, A. J.; Nicodemus, C. F.; Corrigan, C.; Kaye, S. B.; Nestle, F. O.; Gould, H. J.; Spicer, J. F.; Karagiannis, S. N.

In: Clinical and Experimental Allergy, Vol. 41, No. 10, 10.2011, p. 1400-1413.

Research output: Contribution to journalArticle

Rudman, SM, Josephs, DH, Cambrook, H, Karagiannis, P, Gilbert, AE, Dodev, T, Hunt, J, Koers, A, Montes, A, Taams, L, Canevari, S, Figini, M, Blower, PJ, Beavil, AJ, Nicodemus, CF, Corrigan, C, Kaye, SB, Nestle, FO, Gould, HJ, Spicer, JF & Karagiannis, SN 2011, 'Harnessing engineered antibodies of the IgE class to combat malignancy: Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity', Clinical and Experimental Allergy, vol. 41, no. 10, pp. 1400-1413. https://doi.org/10.1111/j.1365-2222.2011.03770.x
Rudman, S. M. ; Josephs, D. H. ; Cambrook, H. ; Karagiannis, P. ; Gilbert, A. E. ; Dodev, T. ; Hunt, J. ; Koers, A. ; Montes, A. ; Taams, L. ; Canevari, S. ; Figini, M. ; Blower, P. J. ; Beavil, A. J. ; Nicodemus, C. F. ; Corrigan, C. ; Kaye, S. B. ; Nestle, F. O. ; Gould, H. J. ; Spicer, J. F. ; Karagiannis, S. N. / Harnessing engineered antibodies of the IgE class to combat malignancy : Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity. In: Clinical and Experimental Allergy. 2011 ; Vol. 41, No. 10. pp. 1400-1413.
@article{36d6457f02234745831543d0c5b7a2b8,
title = "Harnessing engineered antibodies of the IgE class to combat malignancy: Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity",
abstract = "Background IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, Fce{open}RI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-Fce{open}RI complexes on basophils to cause type I hypersensitivity. Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fce{open}RI-mediated type I hypersensitivity. Methods As validated readouts of the potential for MOv18 to cause Fce{open}RI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) Fce{open}RI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. Results Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fce{open}RI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.",
keywords = "Anaphylaxis, Basophil, Cancer therapy, CD63, Degranulation, FRα, Tumour antigen-specific IgE, Type I hypersensitivity",
author = "Rudman, {S. M.} and Josephs, {D. H.} and H. Cambrook and P. Karagiannis and Gilbert, {A. E.} and T. Dodev and J. Hunt and A. Koers and A. Montes and L. Taams and S. Canevari and M. Figini and Blower, {P. J.} and Beavil, {A. J.} and Nicodemus, {C. F.} and C. Corrigan and Kaye, {S. B.} and Nestle, {F. O.} and Gould, {H. J.} and Spicer, {J. F.} and Karagiannis, {S. N.}",
year = "2011",
month = "10",
doi = "10.1111/j.1365-2222.2011.03770.x",
language = "English",
volume = "41",
pages = "1400--1413",
journal = "Clinical and Experimental Allergy",
issn = "0954-7894",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - Harnessing engineered antibodies of the IgE class to combat malignancy

T2 - Initial assessment of Fce{open}RI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity

AU - Rudman, S. M.

AU - Josephs, D. H.

AU - Cambrook, H.

AU - Karagiannis, P.

AU - Gilbert, A. E.

AU - Dodev, T.

AU - Hunt, J.

AU - Koers, A.

AU - Montes, A.

AU - Taams, L.

AU - Canevari, S.

AU - Figini, M.

AU - Blower, P. J.

AU - Beavil, A. J.

AU - Nicodemus, C. F.

AU - Corrigan, C.

AU - Kaye, S. B.

AU - Nestle, F. O.

AU - Gould, H. J.

AU - Spicer, J. F.

AU - Karagiannis, S. N.

PY - 2011/10

Y1 - 2011/10

N2 - Background IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, Fce{open}RI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-Fce{open}RI complexes on basophils to cause type I hypersensitivity. Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fce{open}RI-mediated type I hypersensitivity. Methods As validated readouts of the potential for MOv18 to cause Fce{open}RI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) Fce{open}RI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. Results Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fce{open}RI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

AB - Background IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, Fce{open}RI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-Fce{open}RI complexes on basophils to cause type I hypersensitivity. Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fce{open}RI-mediated type I hypersensitivity. Methods As validated readouts of the potential for MOv18 to cause Fce{open}RI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) Fce{open}RI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. Results Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fce{open}RI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

KW - Anaphylaxis

KW - Basophil

KW - Cancer therapy

KW - CD63

KW - Degranulation

KW - FRα

KW - Tumour antigen-specific IgE

KW - Type I hypersensitivity

UR - http://www.scopus.com/inward/record.url?scp=80052966648&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052966648&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2222.2011.03770.x

DO - 10.1111/j.1365-2222.2011.03770.x

M3 - Article

C2 - 21569129

AN - SCOPUS:80052966648

VL - 41

SP - 1400

EP - 1413

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

SN - 0954-7894

IS - 10

ER -