Pre-clinical evaluation and efficacy studies of a melanin-binding IgM antibody labeled with 188Re against experimental human metastatic melanoma in nude mice.
OBJECTIVE
Currently there is no satisfactory treatment for metastatic melanoma. Radioimmunotherapy (RIT) uses the antigen-antibody interaction to deliver lethal radiation to target cells. Recently we established the feasibility of targeting melanin in tumors with 188-Rhenium ((188)Re)-labeled 6D2 mAb to melanin. Here we carried out pre-clinical development of (188)Re-6D2 to accrue information necessary for a Phase I trial in patients with metastatic melanoma.


RESULTS
TCEP proved to be effective in generating a sufficient number of -SH groups on 6D2 to ensure high radiolabeling yields with (188)Re and preserved its structural integrity. (188)Re-6D2 was quickly cleared from the blood with the half-life of approximately 5 hrs and from the body--with the half-life of 10 hr. The doses of 0.5, 1.0 and 1.5 mCi significantly (p < 0.05) slowed down A2058 tumor growth in nude mice, also causing release of melanin into the extracellular space which could provide additional target for repeated treatments. Transient effects of RIT on WBC and platelet counts resolved by Day 14 post-treatment.


METHODS
Tris(2-Carboxyethyl) Phosphine Hydrochloride (TCEP) was evaluated as potential agent for generation of -SH groups on 6D2 mAb. TCEP-treated 6D2 mAb was radiolabeled with (188)Re and its radiochemical purity and stability was measured by ITLC and HPLC and its immunoreactivity--by melanin-binding ELISA. The pharmacokinetics, therapeutic efficacy and acute hematologic toxicity studies were performed in nude mice bearing lightly pigmented A2058 human metastatic melanoma tumors.


CONCLUSIONS
We have developed radiolabeling and quality control procedures for melanin-binding (188)Re-6D2 mAb which made possible currently an on-going Phase I clinical trial in patients with metastatic melanoma.
Department of Nuclear Medicine, Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA. edadacho@aecom.yu.edu
Ekaterina
E
Dadachova
E
E
Revskaya
M A
MA
Sesay
H
H
Damania
R
R
Boucher
R S
RS
Sellers
R C
RC
Howell
L
L
Burns
G B
GB
Thornton
A
A
Natarajan
G R
GR
Mirick
S J
SJ
DeNardo
G L
GL
DeNardo
A
A
Casadevall
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry*; D008543:Melanins / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes / Q000494:pharmacology; D012211:Rhenium / Q000494:pharmacology
D007075:Immunoglobulin M; D008543:Melanins; D011868:Radioisotopes; D012211:Rhenium; D001205:Ascorbic Acid