Toxicity, immunogenicity, and tumor radioimmunodetecting ability of two human monoclonal antibodies in patients with metastatic colorectal carcinoma.

Abstract

Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.

IgM monoclonal antibody JD118 recognizes an inducible antigen target for human-complement-mediated cytotoxicity against neoplastic B cells

“…Potential disadvantages in using IgM mAb include the increased difficulty in purifying an IgM mAb compared to an IgG mAb and the theoretical problem that the large IgM mAb may have difficulty diffusing into extravascular areas. This latter issue has been examined in two recent imaging trials with radiolabeled human IgM mAb; positive tumor localization in patients with solid tumors was demonstrated [20,23]. There have been no reported clinical trials of mouse IgM in vivo for B cell neoplasms, but treatment of involved bone marrow ex vivo with cytotoxic murine IgM mAb and human complement can selectively lyse tumor cells without negatively affecting growth of normal bone marrow progenitor cells [22,24].…”

Tumour localization and pharmacokinetics of iodine-125 human monoclonal IgM antibody (COU-1) and its monomeric and half-monomeric fragments analysed in nude mice grafted with human tumour

“…Recognition of the human antibody by the murine immune system and differences in the glycosylation of human and murine Ig may be factors leading to faster catabolism of the human IgM and accumulation of antibody and 125I in the liver. Human monoclonal IgM, with a whole-body half-life of 51 h and a plasma half-life of 26 h in patients, does seem to be cleared more slowly in the autologous organism than in mice (Steis et al 1990). The clearance rates of the monomeric and half-monomeric fragment in patient are still unknown.…”

“…Different dehalogenation rates are found in different tissues, from nearly no dehalogenation in the blood to a high dehalogenation rate in the liver (Halpern et al 1988). Although McCabe et al (1988) found a rather low concentration of ~25I in the xenografted colon tumour, they were still able to detect 58% of colon tumour lesions larger than 2 cm in diameter in colon cancer patients (Steis et al 1990). The lower absolute uptake/retention of half-monomeric COU-1 compared to intact and monomeric COU-1 may affect clinical imaging; however, the faster clearance and early favourable tumour-to-normal tissue ratio may be advantageous.…”

Monoclonal Antibody Targeting of Ovarian Carcinoma

“…Therefore, this possibility has to be monitored always, when murine antibodies are administered. In order to overcome xenogeneic mAb immunogenicity, human or humanised (chimeric or CDRgrafted) mAbs [41][42][43] and more recently their respective Fab) and Fv fragments [44,45] have entered diagnostic or therapeutic pilot preclinical/clinical studies. A CDRgrafted human mAb, Hu2PLAP, against PLAP was constructed by incorporating the CDRs from the murine IgG1 antibody H17E2 into a human IgG1 framework.…”