Advantage of dose fractionation in monoclonal antibody-targeted radioimmunotherapy

Journal Article · Wed May 02 04:00:00 EDT 1990 · JNCI, Journal of the National Cancer Institute; (USA)

DOI:https://doi.org/10.1093/jnci/82.9.763· OSTI ID:7099512

Schlom, J; Molinolo, A; Simpson, J F; Siler, K; Roselli, M; Hinkle, G; Houchens, D P; Colcher, D ^[1]

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1. National Cancer Institute, Bethesda, MD (USA)

Monoclonal antibody (MAb) B72.3 IgG was radiolabeled with 131I and administered to female athymic NCr-nu mice bearing the LS-174T human colon adenocarcinoma xenograft to determine if fractionation of MAb dose had any advantage in tumor therapy. In the LS-174T xenograft, only approximately 30%-60% of tumor cells express the B72.3-reactive TAG-72 antigen. The LS-174T xenograft was used to reflect the heterogeneity of the TAG-72 antigen often seen in biopsy specimens from patients. In contrast to a single 600-muCi dose of 131I-B72.3 IgG where 60% of the animals died from toxic effects, two 300-muCi doses of 131I-B72.3 IgG reduced or eliminated tumor growth in 90% of mice, with only 10% of the animals dying from toxic effects. Dose fractionation even permitted escalation of the dose to three doses of 300 muCi of 131I-B72.3 IgG, resulting in even more extensive tumor reduction or elimination and minimal toxic effects. The use of an isotype-matched control MAb revealed a nonspecific component to tumor growth retardation, but the use of the specific B72.3 IgG demonstrated a much greater therapeutic effect. Tumors that had escaped MAb therapy were analyzed for expression of the B72.3-reactive TAG-72 antigen with the use of the immunoperoxidase method; they were shown to have the same antigenic phenotype as the untreated tumors. We verified tumor elimination by killing the test animals after a 7-week observation period and performing histologic examination of tumor sites. We also monitored toxic effects by histologic examination of numerous organs. These studies thus demonstrate the advantage of dose fractionation of a radiolabeled MAb for tumor therapy. We anticipate that the concept of dose fractionation can be practically applied in radioimmunotherapeutic clinical trials with the development and use of recombinant-chimeric MAbs and modified constructs.

• OSTI ID: 7099512
• Journal Information: JNCI, Journal of the National Cancer Institute; (USA), Journal Name: JNCI, Journal of the National Cancer Institute; (USA) Vol. 82:9; ISSN 0027-8874; ISSN JJIND
• Country of Publication: United States
• Language: English

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550604* -- Medicine-- Unsealed Radionuclides in Therapy-- (1980-)
62 RADIOLOGY AND NUCLEAR MEDICINE
ANIMALS
ANTIBODIES
ANTIGENS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BODY
CARCINOMAS
DAYS LIVING RADIOISOTOPES
DIGESTIVE SYSTEM
DISEASES
EXPERIMENTAL NEOPLASMS
FRACTIONATED IRRADIATION
GASTROINTESTINAL TRACT
GLYCOPROTEINS
IMMUNOLOGY
IMMUNOTHERAPY
INTERMEDIATE MASS NUCLEI
INTESTINES
IODINE 131
IODINE ISOTOPES
IRRADIATION
ISOTOPES
LARGE INTESTINE
MAMMALS
MEDICINE
MICE
MONOCLONAL ANTIBODIES
NEOPLASMS
NUCLEAR MEDICINE
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RADIOIMMUNOLOGY
RADIOIMMUNOTHERAPY
RADIOISOTOPES
RADIOLOGY
RADIOTHERAPY
RODENTS
THERAPY
VERTEBRATES