Pharmacokinetics and tumor localization of (111)in-labeled HuCC49DeltaC(H)2 in BALB/c mice and athymic murine colon carcinoma xenograft

Cancer Biother Radiopharm. 2006 Apr;21(2):106-16. doi: 10.1089/cbr.2006.21.106.

Abstract

The primary limitation of IgG antibodies for radioimmunotherapy of solid tumors is their prolonged serum half-life, leading to dose-limiting bone marrow toxicity at doses providing inadequate radiation to the tumor. A humanized C(H)2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49DeltaC(H)2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of (111)In-HuCC49DeltaC(H)2 in BALB/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of (111)In-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent. Immuno-conjugates of HuCC49DeltaC(H)2 and cCC49 prepared with the (111)In chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radio-incorporation with (111)In while retaining greater than 80% immunoreactivity. Blood clearance of (111)In-HuCC49DeltaC(H)2 in BALB/c mice was monoexponential (t(1/2) 5.4 hours) and faster than (111)In-cCC49 (biexponential clearance; t1/2Delta 1.5 hours; t1/2beta 162 hours). The (111)In-HuCC49DeltaC(H)2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for (111)In-HuCC49DeltaC(H)2 and (111)In-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for (111)In- HuCC49DeltaC(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for (111)In-cCC49. However, at 24 hours, blood concentration for (111)In-HuCC49DeltaC(H)2 was less than (111)In-cCC49 (0.9 %ID/g versus 5.2 %ID/g, respectively) with comparable tumor retention (14.4 %ID/g versus 19.0 %ID/g, respectively). Faster blood clearance of (111)In-HuCC49DeltaC(H)2 and tumor localization comparable to that of (111)In-cCC49 provided a fourfold improved tumor-to-blood ratio for (111)In-HuCC49DeltaC(H)2 at 24 hours postinjection.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Neoplasm / immunology
  • Antigens, Neoplasm / immunology
  • Binding, Competitive
  • Colonic Neoplasms / blood
  • Colonic Neoplasms / diagnostic imaging*
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism*
  • Female
  • Glycoproteins / immunology
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Immunotoxins / chemistry
  • Immunotoxins / pharmacokinetics*
  • Indium Radioisotopes / pharmacokinetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pentetic Acid / analogs & derivatives
  • Pentetic Acid / chemistry
  • Radionuclide Imaging
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Antigens, Neoplasm
  • B72.3 antibody
  • Glycoproteins
  • Immunoglobulin G
  • Immunotoxins
  • Indium Radioisotopes
  • tumor-associated antigen 72
  • 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid
  • Pentetic Acid