TY - JOUR
T1 - Evaluation of [225Ac]Ac-DOTA-anti-VLA-4 for targeted alpha therapy of metastatic melanoma
AU - Cortez, Angel
AU - Josefsson, Anders
AU - McCarty, Greg
AU - Shtekler, Abigail E.
AU - Rao, Akhila
AU - Austin, Zachery
AU - Nedrow, Jessie R.
N1 - Funding Information:
The Actinium-225 used in this research was supplied by the Isotope Program within the Office of Nuclear Physics in the Department of Energy's Office of Science. The authors would like to acknowledge the Radiological Physics Division, directed by Dr. George Sgouros, and the Radiology Department at Johns Hopkins University for their support of this project.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Very late antigen 4 (VLA-4; also called integrin α4β1) is overexpressed in melanoma tumor cells with an active role in tumor growth, angiogenesis, and metastasis, making VLA-4 a potential target for targeted alpha therapy (TAT). Methods: An anti-VLA-4 antibody was conjugated to DOTA for [225Ac]Ac-labeling and DTPA for [111In]In-labeling. The resulting agents, [225Ac]Ac- or [111In]In-labeled anti-VLA-4 were evaluated in vitro, including binding affinity, internalization, and colony formation assays as well as in vivo biodistribution studies. In addition, the therapeutic efficacy of [225Ac]Ac-DOTA-anti-VLA-4 was evaluated in a disseminated disease mouse model of melanoma. Results: [111In]In-DTPA-anti-VLA-4 demonstrated high affinity for VLA-4 (Kd = 5.2 ± 1.6 nM). [225Ac]Ac-DOTA-anti-VLA-4 was labeled with an apparent molar activity of 3.5 MBq/nmol and > 95% radiochemical purity. Colony formation assays demonstrated a decrease in the surviving fraction of B16F10 cells treated with [225Ac]Ac-DOTA-anti-VLA-4 compared to control. Biodistribution studies demonstrated accumulation in the VLA-4-positive tumor and VLA-4 rich organs. Therapeutic efficacy studies demonstrated a significant increase in survival in mice treated with [225Ac]Ac-DOTA-anti-VLA-4 as compared to controls. Conclusion: The work presented here demonstrated that [225Ac]Ac-DOTA-anti-VLA-4 was effective as a treatment in mice with disseminated disease, but potentially has dose limiting hematopoietic toxicity. Preliminary studies presented here also supported the potential to overcome this limitation by exploring a pre-loading or blocking dose strategy, to optimize the targeting vector to help minimize the absorbed dose to VLA-4 rich organs while maximizing the dose delivered to VLA-4-positive melanoma tumor cells.
AB - Very late antigen 4 (VLA-4; also called integrin α4β1) is overexpressed in melanoma tumor cells with an active role in tumor growth, angiogenesis, and metastasis, making VLA-4 a potential target for targeted alpha therapy (TAT). Methods: An anti-VLA-4 antibody was conjugated to DOTA for [225Ac]Ac-labeling and DTPA for [111In]In-labeling. The resulting agents, [225Ac]Ac- or [111In]In-labeled anti-VLA-4 were evaluated in vitro, including binding affinity, internalization, and colony formation assays as well as in vivo biodistribution studies. In addition, the therapeutic efficacy of [225Ac]Ac-DOTA-anti-VLA-4 was evaluated in a disseminated disease mouse model of melanoma. Results: [111In]In-DTPA-anti-VLA-4 demonstrated high affinity for VLA-4 (Kd = 5.2 ± 1.6 nM). [225Ac]Ac-DOTA-anti-VLA-4 was labeled with an apparent molar activity of 3.5 MBq/nmol and > 95% radiochemical purity. Colony formation assays demonstrated a decrease in the surviving fraction of B16F10 cells treated with [225Ac]Ac-DOTA-anti-VLA-4 compared to control. Biodistribution studies demonstrated accumulation in the VLA-4-positive tumor and VLA-4 rich organs. Therapeutic efficacy studies demonstrated a significant increase in survival in mice treated with [225Ac]Ac-DOTA-anti-VLA-4 as compared to controls. Conclusion: The work presented here demonstrated that [225Ac]Ac-DOTA-anti-VLA-4 was effective as a treatment in mice with disseminated disease, but potentially has dose limiting hematopoietic toxicity. Preliminary studies presented here also supported the potential to overcome this limitation by exploring a pre-loading or blocking dose strategy, to optimize the targeting vector to help minimize the absorbed dose to VLA-4 rich organs while maximizing the dose delivered to VLA-4-positive melanoma tumor cells.
KW - Actinium
KW - Anti-VLA-4
KW - Metastatic melanoma
KW - Targeted alpha therapy
KW - α4β1
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U2 - 10.1016/j.nucmedbio.2020.07.006
DO - 10.1016/j.nucmedbio.2020.07.006
M3 - Article
C2 - 32799049
AN - SCOPUS:85089272005
SN - 0969-8051
VL - 88-89
SP - 62
EP - 72
JO - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
JF - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
ER -