Biodistribution and preclinical radioimmunotherapy studies using radiolanthanide-labeled immunoconjugates

Abstract

Lutetium‐177 (177Lu), samarium‐153 (153Sm), and yt‐trium‐90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor‐associated antigen TAG‐72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab′)2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA‐DOTA. The authors also review the results of a biodistribution study comparing iodine‐125‐labeled and 177Lu‐labeled CC49 sFv, and the use of 177Lu‐CC49 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab′)2. Biodistribution data obtained in athymic mice bearing LS‐174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab′)2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal‐la‐beled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu‐CC49 was found to delay the growth of established LS‐174T human colon carcinomas in athymic mice at a single dose of 50 μCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 μCi. Dose fractionation experiments revealed that the mice tolerated 750 μCi (3 × 250 μCi, given weekly), whereas > 50% of the mice died after receiving a single administration of ∼ 500 μCi. In iso‐type‐matched control experiments, a large differential in the therapeutic effects was observed between 177Lu‐la‐beled control antibody and CC49. Cancer 1994; 73:993–8.

Therapeutic efficacy of 177Lu‐CHX‐A″‐DTPA‐hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

“…RIT offers a therapeutic strategy for the selective delivery of radiation to tumors, while limiting the systemic effects of radiation on normal tissues [30]. The radioisotope 177 Lu has been identified as a promising alternative to established b-emitters such as 131 I and 90 Y, with physical properties amenable to RIT of small lesions where clinical efficacy of RIT is most likely [5,38,39]. The limited efficacy of RIT in the treatment of solid tumors has lead to the investigation of various methods for improving the therapeutic efficacy of RIT [8].…”

In vivo Evaluation of 177Lu- and 67/64Cu-Labeled Recombinant Fragments of Antibody chCE7 for Radioimmunotherapy and PET Imaging of L1-CAM-Positive Tumors

“…Lu-labeled fragments was done, because development of radiolabeled antibody fragments has to take into account availability of the chosen radionuclides in addition to good protein production yields and convenience of labeling protocols. Now, 177 Lu is more widely available than 67 Cu and has been successfully used for labeling of antibody fragments (9,42) and peptides (29). In this study, almost identical procedures were used for radiolabeling with the two nuclides and fully immunoreactive fragments with similar specific activities were obtained.…”

Emergence and present status of Lu-177 in targeted radiotherapy: the Indian scenario

“…While the use of 177 Lu for radiotherapy has been reported earlier by a few researchers [15][16][17][18][19], the concerted efforts to explore the potential applicability of this isotope in designing agents for therapeutic applications, more specifically targeted radiotherapy, was realized as early as in 2000, in the Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC). A logical outcome therefore led to research towards envisaging methods to produce this logistically suitable isotope in adequate quantities and specific activities using the present reactor facilities in our Institute.…”