Specific targeting of human integrin α(v)β (3) with (111)In-labeled Abegrin™ in nude mouse models

The cell adhesion molecule integrin α(v)β(3) is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin α(v)β(3) monoclonal antibody, was currently in clinical trials for cancer therapy. Herein, we labeled Abegrin™ with (111)In, evaluated the in vitro and in vivo characteristics, and investigated whether the expression of integrin α(v)β(3) in tumors could be imaged with (111)In-labeled Abegrin™.

The binding affinity and specificity of Abegrin™ was analyzed using U87MG glioblastoma cells. Abegrin™ was coupled with 1,4,7,10-tetraazadodecane-N,N',N",N'″-tetraacetic acid (DOTA) for (111)In radiolabeling. γ Imaging of (111)In-DOTA-Abegrin™ was carried out in nude mice bearing both integrin α(v)β(3)-positive U87MG and integrin α(v)β(3)-negative HT-29 tumors. Biodistribution and blocking studies of (111)In-DOTA-Abegrin™ were investigated in U87MG tumor-bearing nude mice.

Abegrin™ exhibited high-binding affinity to human integrin α(v)β(3) expressed on U87MG cells (K (d) of 0.35 ± 0.06 nM). The antibody retained antigen-binding affinity/specificity after DOTA conjugation. γ Imaging showed that the tumor uptake of (111)In-DOTA-Abegrin™ in integrin α(v)β(3)-positive U87MG tumors was much higher than that in integrin α(v)β(3)-negative HT-29 tumors. In the HT-29 tumors, Abegrin™ was mainly nonspecifically accumulated around the blood vessels, while in the U87MG tumors, besides the nonspecific tumor retention, Abegrin™ also specifically bound the human integrin α(v)β(3) expressed on the tumor cells. Biodistribution and blocking studies exhibited that the U87MG tumor uptake of (111)In-DOTA-Abegrin™ decreased from 14.12 ± 0.44 to 6.93 ± 0.94 percentage of injected dose per gram of tissue after coinjection of excess dose of cold Abegrin™, which confirmed the in vivo integrin α(v)β(3) binding specificity of (111)In-DOTA-Abegrin™.

Abegrin™ showed specific binding to human integrin α(v)β(3) expressed on the tumor cells. (111)In-DOTA-Abegrin™ can specifically target the human integrin α(v)β(3) expression in the nude mouse model. (111)In-DOTA-Abegrin™ has a potential for clinical translation as an agent for integrin α(v)β(3)-positive tumor imaging, evaluating tumor angiogenic status and monitoring the therapeutic efficacy of Abegrin™-based cancer therapy.