MONOCLONAL-ANTIBODIES LABELED WITH RE-186 USING THE MAG3 CHELATE - RELATIONSHIP BETWEEN THE NUMBER OF CHELATED GROUPS AND BIODISTRIBUTION CHARACTERISTICS
Fb. Vangog et al., MONOCLONAL-ANTIBODIES LABELED WITH RE-186 USING THE MAG3 CHELATE - RELATIONSHIP BETWEEN THE NUMBER OF CHELATED GROUPS AND BIODISTRIBUTION CHARACTERISTICS, The Journal of nuclear medicine, 37(2), 1996, pp. 352-362
Our previous studies on the preparation of Re-186-MAb conjugates for c
linical radioimmunotherapy (RIT) were extended with the aim to derive
conjugates which have a high Re:MAb molar ratio, are stable in vitro a
nd in vivo, have favorable biodistribution characteristics and can be
used together with Tc-99m-MAb conjugates as a matched pair in combined
radioimmunoscintigraphy/RIT studies. Methods: Rhenium and Tc-99m-conj
ugates of intact MAb E48 were prepared according to our previously des
cribed multistep procedure using the MAG3 chelate and analyzed by prot
ein mass spectrometry for the number of chelate molecules coupled to t
he MAb. For biodistribution analysis, tumor-free nude mice were simult
aneously injected with Re-186-, (TC)-T-99m/(TC)-T-99- and/or (125)l-la
beled E48 IgG and dissected 1-48 hr postinjection. Results: Rhenium-18
6-MAb conjugates with up to 20 Re-MAG3 groups per MAb molecule were pr
epared with an overall radiochemical yield of 40%-60%. The conjugates
did not contain empty MAG3 groups and no aggregates were formed. Only
conjugates with a Re-186-MAG3:MAb molar ratio higher than 12 demonstra
ted slightly impaired immunoreactivity to a maximum of 15% decrease at
the 20:1 molar ratio. Biodistribution experiments revealed that a pro
portion of the conjugate became rapidly eliminated from the blood for
conjugates with a Re-MAG3:MAb molar ratio higher than 8. In this case,
an increased uptake of activity was observed in the liver and intesti
nes. The Tc-99m/Tc-99-MAb conjugates showed a similar enhanced blood c
learance when containing more than eight Tc-MAG3 groups, while dual la
beling of MAbs revealed that the in vivo stability of the conjugated R
e-MAG3 complex itself does not differ from the corresponding Tc-MAG3 c
omplex. Conclusion: With the method described in this study, it is pos
sible to prepare Re-186-MAG3-MAb conjugates that fulfil all the aforem
entioned criteria for use in clinical RIT. Coupling of too many metal-
MAG3 groups to MAbs results in rapid blood clearance. At the same meta
l-MAG3:MAb molar ratio, Tc-99m/Tc-99-MAb conjugates show a similar pha
rmacokinetic behavior as Re-186-MAb conjugates and can thus be used to
predict the localization of Re-186-labeled MAbs and make dosimetric p
redictions in individual patients.