Optimal Saturated Neuropilin-1 Expression in Normal Tissue Maximizes Tumor Exposure to Anti-Neuropilin-1 Monoclonal Antibody

Abstract

Background: As involved in tumor angiogenesis, Neuropilin Receptor type-1 (NRP-1) serves as an attractive target for cancer molecular imaging and therapy. Widespread expression of NRP-1 in normal tissues may affect anti-NRP-1 antibody tumor uptake. Objective: To assess a novel anti-NRP-1 monoclonal antibody A6-11-26 biodistribution in NRP-1 positive tumor xenograft models to understand the relationships between dose, normal tissue uptake and tumor uptake. Methods: The A6-11-26 was radiolabeled with 131I and the mice bearing U87MG xenografts were then administered with 131I-labelled A6-11-26 along with 0, 2.5, 5, and 10mg·kg-1 unlabelled antibody A6-11-26. Biodistribution and SPECT/CT imaging were evaluated. Results: 131I-A6-11-26 was synthesized successfully by hybridoma within 60min. It showed that most of 131IA6- 11-26 were in the plasma and serum (98.5 ± 0.16 and 88.9 ± 5.84, respectively), whereas, less in blood cells. For in vivo biodistribution studies, after only injection of 131I-A6-11-26, high levels of radioactivity were observed in the liver, moderate level in lungs. However, liver and lungs radioactivity uptakes could be competitively blocked by an increasing amount of unlabeled antibody A6-11-26, which can increase tumor radioactivity levels, but not in a dose-dependent manner. A dose between 10 and 20mg·kg-1 of unlabeled antibody A6-11-26 may be the optimal dose that maximized tumor exposure. Conclusion: Widespread expression of NRP-1 in normal tissue may affect the distribution of A6-11-26 to tumor tissue. An appropriate antibody A6-11-26 dose would be required to saturate normal tissue antigenic sinks to achieve acceptable tumor exposure.

Preclinical Evaluation of a Novel 99mTc-Labeled CB86 for Rheumatoid Arthritis Imaging

“…A high expression of the target in a normal organ might appreciably influence the imaging results, especially when the target level in the lesion is low. After the optimization of spiking doses was administered to saturate the target expression in normal organ, an increase lesion–normal ratio could be achieved. , For in vivo blocking study (Figure ), 99m Tc-DTPA-CB86 was co-injected with a large excess (300 μg) of unlabeled DTPA-CB86 to saturate endogenous and overexpressed TSPO. The co-injection of DTPA-CB86 reduces the uptake of 99m Tc-DTPA-CB86 in several tissues including liver, lung, heart, intestine, left inflammatory ankle, etc., indicating that there is a significant difference between blocking and unblocking group in these tissues ( P < 0.05), whereas the kidney, muscle, and bone uptakes are not significantly different between the blocking and unblocking group ( P > 0.05).…”