Tumor cell retention of antibody Fab fragments is enhanced by an attached HIV TAT protein-derived peptide.
Two peptide analogs of the 37-62 sequence region of the HIV TAT protein bind tightly to the surface of A431 breast carcinoma cells. After conjugation to either of two poorly internalized anti-tumor antibody Fab fragments, the analogs enhanced the in vitro cell surface retention and internalization of the Fab fragments to the level of the whole antibodies. This was at the expense of some binding specificity in the case of 1.6 peptides/NRLU-10 Fab, but not in the case of 1.1 peptides/Fab. Enhanced retention may occur by enhanced bivalent binding of the Fab fragments. The internalized fraction of free peptide, but not of the Fab conjugates, is enhanced by chloroquine. The conjugates which were less specific for tumor cell binding may be useful for enhanced retention/internalization of specifically acting agents, for use at specific sites of injection, or against pre-separated target cell populations, while the more specific conjugate may be of interest for further development.
Anderson
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NeoRx Corporation, Seattle, WA 98119.
Nichols
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E
Manger
R
R
Woodle
D
D
Barry
M
M
Fritzberg
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AR
D000595:Amino Acid Sequence; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D003110:Colonic Neoplasms; D004797:Enzyme-Linked Immunosorbent Assay; D015696:Gene Products, tat / Q000378:metabolism*; D006678:HIV / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007700:Kinetics; D008545:Melanoma; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D002250:Carbon Radioisotopes; D015696:Gene Products, tat; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; D002738:Chloroquine