Phase I trial of murine monoclonal antibody L6 in breast, colon, ovarian, and lung cancer.

Abstract

Murine monoclonal antibody (MAb) L6 binds to an antigen expressed on the surface of breast, colon, ovary, and nonsmall-cell lung cancer. This antibody effects antibody-dependent cellular cytotoxicity (ADCC) with human mononuclear cells and complement-dependent cytotoxicity (CDC) with human complement. Because of these activities, we conducted a phase I trial of MAb L6 in patients with advanced cancer. Nineteen patients whose tumors highly expressed antigen were selected for this trial. Eighteen were evaluable. MAb L6 was administered at dose levels ranging from 5 mg/m2/d to 400 mg/m2/d for 7 days and was well tolerated. The only side effects detected were fever and headaches at the highest dose levels. The serum half-life of L6 was directly related to dose and ranged from a mean of 7.7 hours at 5 mg/m2/d to 29.1 hours at 400 mg/m2/d. Peak serum concentrations ranged from 0.22 micrograms/mL to 362 micrograms/mL. Biopsies at the end of treatment showed L6 to localize well to tumor cells with apparent in vivo saturation occurring at dose levels above 100 mg/m2/d. Thirteen patients formed human antimouse antibodies (HAMA), some as early as day 13. One patient with recurrent breast cancer on the chest wall achieved a complete remission. The response was first noted at 5 weeks and a pathologic complete remission occurred at 14 weeks. Because of its favorable binding properties and the encouraging clinical effect observed, future evaluation of this MAb appears warranted.

Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis

“…Attempts to use unconjugated C-activating MAbs in the therapy of solid tumours have therefore been tried (Houghton et al, 1985;Goodman et al, 1990;Riethmuller et al, 1993;Rubin, 1993). Although the MAbs bind to the tumour cells in vivo (Houghton et al, 1985;Rubin, 1993) and mediate local C deposition (Houghton et al, 1985), the therapeutic efficiency is limited (Houghton et al, 1985;Riethmuller and Johnson, 1992;Riethmuller et al, 1993;Rubin, 1993) and correlates negatively with the volume of the tumour mass (Riethmuller et al, 1993).…”

“…As a tumour arising from a 'non-essential' organ that remains primarily confined to the peritoneal cavity, ovarian cancer is particularly well suited for monoclonal antibody (MAb) adjuvant immunotherapy (Rubin, 1993). Numerous clinical antibody treatment trials have, unfortunately, failed to lead to any consistent pattern of clinical response (Hamilton et al, 1987;Goodman et al, 1990;Guadagni et al, 1993;Rubin, 1993). Consequently, the cells' ability to resist C attack may at least partly explain the lack of therapeutic efficiency of tumour-specific MAbs (Bj0rge et al, 1996).…”

Cloning and expression of the tumor-associated antigen L6.

“…7; J. R. Rillema, personal communication), the fact that it has a very high expression on tumors has led to several clinical studies with mAb L6. A phase I clinical study carried out in patients with recurrent cancer of either breast, colon, lung, or ovary showed that the murine mAb L6 was well tolerated and effectively localized to the tumor in vivo and that one patient, with recurrent breast cancer on the chest wall, underwent complete, albeit temporary, remission (8). In other studies, murine or chimeric (mouse-human) L6 antibodies were labeled with 1311 and shown to deliver sufficient amounts of radioactivity to tumors to be of therapeutic interest; promising findings have been obtained in initial studies in which patients were given therapeutic doses of radiolabeled chimeric L6 (9).…”

Novel Anti-TM4SF1 Antibody–Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature

“…It is also highly expressed by many different human cancer cells (7,10) and has important roles in cancer initiation, migration, and invasion (38). Earlier studies with L6, an antibody targeting human TM4SF1, exhibited low toxicity and gave promising results in mouse tumor xenografts and in a small number of cancer patients, presumably via mechanisms involving CDC and ADCC (21,39). Together these findings suggested that therapy could be enhanced by targeting TM4SF1 with an ADC approach.…”

“…The clinical experience with L6 and chL6 (and their radio-conjugated counterparts) is also consistent with our mouse data. Although L6 did not carry a payload, it was competent to trigger CDC and ADCC, accumulated in endothelial cell-rich tissues such as lungs, and exhibited little toxicity in patients (21,39). A number of tubulin inhibitors, including vinca alkaloids, auristatins, taxanes, tubulysin, and combretastatins, have been extensively researched and developed as antiangiogenic drugs, and the resistance of normal endothelium to such agents has been well documented in the clinic (28)(29)(30).…”