Interferon-alpha-2b immunoconjugate for improving immunoscintigraphy and immunotherapy.
A pretreatment with a single dose of an immunoconjugate (IC) that promises to enhance tumor uptake and decrease liver uptake of radiolabeled monoclonal antibodies (MAbs) might be of use in radioimmunodetection and radioimmunotherapy (RIT). We have shown previously that an interferon (IFN)-MAb (1:1) immunoconjugate (IC) enhances tumor uptake by a factor of 2 or more and reduces liver uptake by 50% in nude mice bearing human tumors. The aim of this study was to determine whether IFN modulates antigenic expression and to ascertain the most effective route of its administration, the optimal quantity to be administered, and the optimal duration of time to lapse between the administration of IC and the radiolabeled MAb.


METHODS
IFN-alpha-2b and anticarcinoembryonic antigen-F6 (IgG2a) MAb were conjugated (1:1), and F(ab')2 of the MAb was labeled with 99mTc. Human colorectal tumors were grown in nude mice by implanting 5 x 10(6) LS174T confluent cells grown in culture. Mice, 5 in each group, received 20 x 10(3) IU intravenously, intramuscularly, or intraperitoneally and 40 x 10(3), 60 x 10(3), and 80 x 10(3) IU intravenously 30 min before the intravenous administration of 25.9 MBq 99mTc/20 microg F(ab')2. Mice in the control groups received 99mTc-F(ab')2 but not the conjugate. Twenty-four hours later mice were killed and imaged, and tissues were removed for quantitative (percentage injected dose/g [% ID/g]) distribution of 99mTc.


RESULTS
In all conjugate-receiving mice, the tumor uptake was higher and the liver uptake was lower (P < 0.01) than that in the control mice with the exception of liver uptake, which was not significantly different in mice receiving 80 x 10(3) IU conjugate. The optimal results were apparent in mice pretreated with 40 x 10(3) IU conjugate in which tumor uptake was enhanced by a factor of 2.3 (4.8 +/- 0.5 %ID/g versus 11 +/- 0.7 %ID/g; P < 0.01). The renal uptake remained unchanged, and the tumor-to-muscle ratios increased from 11.5 +/- 6.8 to 14.6 +/- 3.9, and the tumor-to-blood ratios increased from 4.4 +/- 1.8 to 8.3 +/- 2.4. The liver uptake decreased from 9.5% +/- 1% to 5% +/- 1.6%. Results were attributed to enhanced tumor blood flow, increased antigenic expression, and blocking of hepatic nonspecific Fc receptors.


CONCLUSIONS
A pretreatment with IFN-MAb conjugate is a worthwhile approach to consider in radioimmunoscintigraphy and RIT.
Pallela
V R
VR
Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.
Rao
S P
SP
Thakur
M L
ML
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy; D004305:Dose-Response Relationship, Drug; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D011994:Recombinant Proteins; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015609:Organotechnetium Compounds; D011994:Recombinant Proteins