Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer

Modjtahedi, Helmout; Hickish, Tamas; Nicolson, Margery; Moore, J.; Styles, JM; Eccles, Suzanne A.; Jackson, Elise; Salter, Janine; Sloane, J P; Spencer, Loreto; Priest, K.; Ie, Smith; Dean, Christopher; Gore, M.

doi:10.1038/bjc.1996.40

Cited by 94 publications

(39 citation statements)

References 29 publications

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“…In that trial, no serious toxicity was observed and four patients developed human anti-rat antibodies. Biopsies obtained from metastatic lesions showed localization of MAb ICR62 to the membranes of tumor cells, more prominently at higher doses (Modjtahedi et al, 1996). The fully human anti-EGF receptor mAb, ABX-EGF, has now entered phase I clinical trials (Yang et al, 2000).…”

Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

“…The need to ®nd an optimal biological dose for patients treated with these antibodies emphasizes the relevance of developing reliable biological markers in trials that evaluate agents acting on the EGFr. Although these early phase I trials with IMC-C225 did not include the analysis of biological markers, other trials with anti-EGFr antibodies and follow up studies with C225 and other anti-EGFr MAbs have shown that antibody binding to tumor EGFr and saturation of the receptors can be achieved (Modjtahedi et al, 1996;Perez-Soler et al, 1994. The pharmacokinetic ®ndings with C225 are in agreement with a prior phase I single dose clinical trial with a di erent murine anti-EGFr MAb, RG 83852, in patients with non-small cell lung cancer or head and neck tumors (Perez-Soler et al, 1994).…”

Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

“…In another Phase I trial, the rat anti-EGFr MAb ICR62 was evaluated in 20 patients with head and neck or lung cancer (Modjtahedi et al, 1996). This antibody e ectively blocks the binding of EGF, TGF-a and HB-EGF to the EGFr, inhibits the growth of cultured …”

Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

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The EGF receptor family as targets for cancer therapy

2000

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Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments. In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and`chimeric' and`humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation therapy and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer. Oncogene (2000) 19, 6550 ± 6565.

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Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

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The EGF receptor family as targets for cancer therapy

2000

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“…non-small-cell lung cancer (NSCLC) is an aggressive solid tumour associated with a poor prognosis since surgery or chemotherapy is only beneficial in a fraction of all cases. Antibody-based therapy has been of limited success, but has been described using murine antibodies against targets such as the EGF-receptor in squamous cell carcinoma (Modjtahedi et al, 1996) or epithelial glycoprotein-2 for adenocarcinoma (Zimmermann et al, 1997). Such monoclonal antibodies probably may act by interfering in tumour cell signalling or through activation of complement and/or Fc receptor bearing cells.…”

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confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

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“…Over-expression of the epidermal growth factor receptor and p185 erbB-2 has been reported in a wide variety of human malignancies (Modjtahedi and Dean, 1994;Hynes and Stern, 1994) and has been found to correlate with poor prognosis in patients bearing these tumours. Importantly, these molecules have been used as targets for the therapy of human disease (Baselga et al, 1996;Modjtahedi et al, 1996). Relatively little is known about the expression of the recently discovered, related receptor, erbB-4 and its importance in human malignancy but a group of ligands, neuregulins, which bind to and activate this receptor have been described.…”

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confidence: 99%

Two erbB-4 transcripts are expressed in normal breast and in most breast cancers

et al. 1998

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ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT ± PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which ampli®ed a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the`full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with di erent intracellular signalling pathways and therefore in¯uence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the Cterminal transcripts as CT-a (full-length) and CT-b which lacks the PI3K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.

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Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer

Cited by 94 publications

References 29 publications

The EGF receptor family as targets for cancer therapy

The EGF receptor family as targets for cancer therapy

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Two erbB-4 transcripts are expressed in normal breast and in most breast cancers

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