Avidity-mediated enhancement of in vivo tumor targeting by single-chain Fv dimers.
Radiolabeled single-chain Fv (sFv) molecules display highly specific tumor retention in the severe combined immunodeficient (SCID) mouse model; however, the absolute quantity of sFv retained in the tumors is diminished by the rapid renal elimination resulting from the small size of the sFv molecules (Mr 27,000) and by dissociation of the monovalent sFv from tumor-associated antigen. We previously reported significant improvement in tumor retention without a loss of targeting specificity on converting monovalent sFv into divalent [(sFv')2] dimers, linked by a disulfide bond between COOH-terminal cysteinyl peptides engineered into the sFv'. However, our data for enhanced dimer localization in tumors could not distinguish between the contributions of enhanced avidity and increased systemic retention associated with the larger size of 54 kDa [(sFv')2] dimers relative to 27-kDa sFv. In this investigation, we have compared tumor targeting of divalent anti-c-erbB-2/HER2/neu 741F8-1 (sFv')2 homodimers with monovalent 741F8/26-10 (sFv')2 heterodimers (Mr 54,000) and 741F8 sFv monomers (741F8 sFv has binding specificity for erbB-2/HER2/neu and 26-10 sFv specificity for digoxin and related cardiac glycosides). These studies allowed us to distinguish the dominant effect of valency over molecular weight in accounting for the superior tumor retention of 741F8-1 (sFv')2 homodimers. Each of the radioiodinated species was administered i.v. to SCID mice bearing SK-OV-3 human tumor xenografts and tumor localization at 24 hours post i.v. injection was determined for 125I-741F8-1 (sFv')2 (3.57 %ID/g), 125I-741F8/26-10 (sFv')2 (1.13 %ID/g), and 125I-741F8-1 sFv (1.25 %ID/g). These findings substantiate that the improved tumor retention of (sFv')2 homodimers over sFv monomers results from the availability of dual binding sites rather than from the slower systemic clearance of homodimers.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. gp_adams@fccc.edu
Gregory P
GP
Adams
Mei-Sheng
MS
Tai
John E
JE
McCartney
James D
JD
Marks
Walter F
WF
Stafford
L L
LL
Houston
James S
JS
Huston
Louis M
LM
Weiner
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity; D000918:Antibody Specificity; D019281:Dimerization; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011877:Radionuclide Imaging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007128:Immunoglobulin Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; C055966:immunoglobulin Fv