Radioimmunoscintigraphy with technetium-99m labelled monoclonal antibody, 1A3, in colorectal cancer

Granowska, M.; Britton, K. E.; Mather, S. J.; Morris, Greg; Ellison, David H.; Soobramoney, S.; Talbot, I. C.; Northover, J. M. A.

doi:10.1007/bf00181760

Cited by 43 publications

(11 citation statements)

References 36 publications

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“…Historically, tumor-bound CEA has been used for cancer imaging and in vaccine and antibody-based therapeutic approaches for cancer treatment. [53][54][55][56] The antigen is limited to the apical surface and luminal portion of adult colonic epithelium under normal physiological conditions, but is overexpressed and loses its polarized distribution in CRC and other cancers resulting in expression of CEA over the entire cell surface. 57 This distribution in normal and neoplastic cells may result in specific targeting of CEA-positive tumor cells and sparing of normal colonic epithelium where T cell traffic is restricted to basolateral surfaces by the tight junctions separating apical and basolateral membranes.…”

Section: Introductionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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Section: Introductionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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“…Earlier work from our laboratory has shown that the antibody PR1A3, which is specific for membrane-bound carcinoembryonic antigen (CEA, formally designated CEACAM5), elicits ADCC against CEA-positive CRC cell lines even in the presence of super-physiological levels of free CEA (Durbin and Bodmer, 1987;Durbin et al, 1994;Conaghan et al, 2008). CEA is present on a high proportion of colorectal cancers, in which it is accessible to intravenously administered antibody, whereas in normal colorectal epithelium, due to the apical localisation of the antigen, it is not (Granowska, 1993). Radioconjugates targeting CEA have been used in early phase clinical trials in CRC (Wong et al, 2004;Liersch et al, 2005), but there is so far no unconjugated anti-CEA antibody licensed for treatment (Blumenthal et al, 2008).…”

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confidence: 99%

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Ashraf

Umaña²,

Mössner³

et al. 2009

Br J Cancer

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BACKGROUND: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested. METHODS: The antibody was modified using EBNA cells cotransfected with b-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes. RESULTS: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model. CONCLUSION: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial.

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“…There have been many monoclonal antibodies developed to detect CRC antigens, with sensitivity ranging from 74% to 92%. These antigens include B72.3, carcinoembryonic antigen (CEA), BW431/21 and PR1A3 [37][38][39][40] . CEA molecules break off the colonic columnar cell membrane and circulate in the blood stream.…”

Section: Radioimmunoscintigraphymentioning

confidence: 99%

The impact of new technology on surgery for colorectal cancer

Makin¹,

Breen²,

Monson³

2001

WJG

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Advances in technology continue at a rapid pace and affect all aspects of life, including surgery. We have reviewed some of these advances and the impact they are having on the investigation and management of c o l o r e c t a l c a n c e r . M o d e r n e n d o s c o p e s , w i t h magnifying, variable stiffness and localisation capabilities are making the primary investigation of colonic cancer easier and more acceptable for patients. Imaging investigations looking at primary, metastatic and recurrent disease are shifting to digital data sets, which can be stored, reviewed remotely, potentially fused with other modalities and reconstructed as 3 dimensional (3D) images for the purposes of advanced diagnostic interpretation and computer assisted surgery. They include virtual colonoscopy, trans-rectal ultrasound, magnetic resonance imaging, positron emission tomography and radioimmunoscintigraphy. Once a colorectal carcinoma is diagnosed, the treatment options available are expanding. Colonic stents are being used to relieve large bowel obstruction, either as a palliative measure or to improve the patient's overall condition before definitive surgery. Transanal endoscopic microsurgery and minimally invasive techniques are being used with similar outcomes and a lower mortality, morbidity and hospital stay than open trans-abdominal surgery. Transanal endoscopic microsurgery allows precise excision of both benign and early malignant lesions in the mid and upper rectum. Survival of patients with i n o p e r a b l e h e p a t i c m e t a s t a s e s f o l l o w i n g radiofrequency ablation is encouraging. Robotics and telemedicine are taking surgery well into the 21 st century. Artificial neural networks are being developed to enable us to predict the outcome for individual patients. New technology has a major impact on the way we practice surgery for colorectal cancer.Subject headings colorectal neoplasms; technology; surgery; radiology

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Radioimmunoscintigraphy with technetium-99m labelled monoclonal antibody, 1A3, in colorectal cancer

Cited by 43 publications

References 36 publications

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

The impact of new technology on surgery for colorectal cancer

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