Journal
NATURE BIOTECHNOLOGY
Volume 25, Issue 8, Pages 921-929Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt1320
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Here we show that fusion of two complementarity-determining regions ( CDRs), V(H)CDR1 and V(L)CDR3, through a cognate framework region ( V(H)FR2) yields mimetics that retain the antigen recognition of their parent molecules, but have a superior capacity to penetrate tumors. The antigen-recognition abilities of these similar to 3 kDa mimetics surpass those of comparable fragments lacking the framework region. In vivo activities of the mimetics suggests that the structural orientation of their CDRs approximates the conformation of the CDRs in the complex of the parent antibody with antigen. We linked the antibody mimetics to the bacterial toxin colicin la to create fusion proteins called pheromonicins,'' which enable targeted inhibition of tumor growth. In mice bearing human malignant tumors, pheromonicins directed against tumor-specific surface markers show greater capacity to target and penetrate tumors than their parent antibodies. Rational recombination of selected V-H/ V-L binding sites and their framework regions might provide useful targeting moieties for cytotoxic cancer therapies.
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