Journal
BIOCONJUGATE CHEMISTRY
Volume 19, Issue 1, Pages 89-96Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bc700161p
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Funding
- NCI NIH HHS [P01 CA043904, P01 CA043904-07A10001, CA43904] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P01CA043904] Funding Source: NIH RePORTER
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Radiolabeled anti-carcinoembryonic antigen (CEA) antibodies have the potential to give excellent images of a wide variety of human tumors, including tumors of the colon, breast, lung, and medullar thyroid. In order to realize the goals of routine and repetitive clinical imaging with anti-CEA antibodies, it is necessary that the antibodies have a high affinity for CEA, low cross reactivity and uptake in normal tissues, and low immunogenicity. The humanized anti-CEA antibody hT84.66-M5A (M5A) fulfills these criteria with an affinity constant of > 10(10) M-1, no reactivity with CEA cross-reacting antigens found in normal tissues, and >90% human protein sequence. A further requirement for routine clinical use of radiolabeled antibodies is a versatile method of radiolabeling that allows the use of multiple radionuclides that differ in their radioemissions and half-lives. We describe a versatile bifunctional chelator, DO3A-VS (1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane) that binds a range of radiometals including In-111 for gamma-ray imaging and Cu-64 for positron emission tomography (PET), and which can be conjugated with negligible loss of immunoreactivity either to sulfhydryls (SH) in the hinge region of lightly reduced immunoglobulins or surface lysines (NH) of immunoglobulins. Based on our correlative studies comparing the kinetics of radiolabeled anti-CEA antibodies in murine models with those in man, we predict that Cu-64-labeled intact, humanized antibodies can be used to image CEA positive tumors in the clinic.
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