In:
Anti-Cancer Agents in Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 18, No. 1 ( 2018-03-16), p. 146-153
Abstract:
Objective: Monoclonal antibodies (mAbs) have been radiolabeled with a variety of radioisotopes
utilizing various kinds of bi-functional chelating agents (BFCAs) with an aim to develop suitable agents for radioimmunotherapy. The number of BFCA moieties present per antibody molecule plays a significant role in
determining the pharmacokinetics and immunoreactivity exhibited by the radiolabeled antibodies. The objective of the present study is to evaluate the effect of the number of BFCA moieties present per antibody molecule on
the pharmacokinetics and immunoreactivity of the 177Lu-labeled Rituximab. Methods: Three different mAb-BFCA conjugates were prepared using different molar ratios of Rituximab
(mAb) to p-NCS-benzyl-DOTA (BFCA) viz. 1:5, 1:10 and 1:50 employing different reaction conditions. Studies were carried out to determine the average number of BFCAs attached per mAb molecule. All the three
mAb-BFCA conjugates were labeled with 177Lu(III) and were subsequently evaluated in normal Swiss mice to ascertain their respective pharmacokinetic behavior. In-vitro studies were also performed in Raji cell lines (human
burkitt's lymphoma) for determining the effect of increasing number of BFCAs attached per mAb molecule on the immunoreactivity of the resultant 177Lu-labeled mAb-BFCA complexes. Results: 177Lu-labeled mAb-BFCA complex prepared corresponding to 1:50 mAb to BFCA ratio exhibited the
least non-specific uptake and rapid clearance from majority of the organs, but also exhibited least immunoreactive fraction (IRF = 19.37%). On the other hand, 177Lu-labeled mAb-BFCA complex prepared corresponding
to 1:5 mAb to BFCA ratio exhibited the highest non-specific uptake and slower clearance pattern, but highest IRF (71.17%). 177Lu-labeled mAb-BFCA complex prepared corresponding to 1:10 mAb:BFCA ratio
exhibited intermediate pharmacokinetic behaviour with moderate IRF (53.05%). Conclusions: The present study indicates that antibody to BFCA ratio plays a crucial role in determining the
immunoreactivity and pharmacokinetic behavior of the radiolabeled antibodies and must be prudently chosen for their successful therapeutic application.
Type of Medium:
Online Resource
ISSN:
1871-5206
DOI:
10.2174/1871520617666170725164530
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2018
SSG:
15,3
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