Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity

TY - JOUR

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

T2 - initial assessment of FcɛRI-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, James

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, Fc epsilon 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 alpha (FR alpha), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FR alpha and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FR alpha-MOv18-IgE-receptor-Fc epsilon RI complexes on basophils to cause type I hypersensitivity.Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fc epsilon RI-mediated type I hypersensitivity.Methods As validated readouts of the potential for MOv18 to cause FceRI-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 (alpha beta gamma 2) FceRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo.Results Serum FR alpha levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FR alpha, or of healthy volunteer (n = 14) or ovarian carcinoma patient (n = 32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FR alpha-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 FR alpha (n = 5).Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fc epsilon 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, Fc epsilon 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 alpha (FR alpha), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FR alpha and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FR alpha-MOv18-IgE-receptor-Fc epsilon RI complexes on basophils to cause type I hypersensitivity.Objective To assess the propensity for MOv18 used in a therapeutic setting to cause Fc epsilon RI-mediated type I hypersensitivity.Methods As validated readouts of the potential for MOv18 to cause FceRI-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 (alpha beta gamma 2) FceRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo.Results Serum FR alpha levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FR alpha, or of healthy volunteer (n = 14) or ovarian carcinoma patient (n = 32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FR alpha-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 FR alpha (n = 5).Conclusion and Clinical Relevance These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, Fc epsilon RI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

U2 - 10.1111/j.1365-2222.2011.03770.x

DO - 10.1111/j.1365-2222.2011.03770.x

M3 - Article

C2 - 21569129

SN - 0954-7894

VL - 41

SP - 1400

EP - 1413

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

IS - 10

M1 - N/A

ER -