ReviewA new era for radiolabeled antibodies in cancer?
Introduction
Radioimmunotherapy (RIT) using systemically administered monoclonal antibodies (MoAbs) linked to radionuclides is a promising approach for treating metastatic cancer. RIT can be regarded as ‘smart’ radiotherapy because of specific targeting of malignant lesions, known or occult. The underlying concept of RIT has been extensively reviewed 1, 2, 3. Because of selective concentration of the MoAb — and thus of the radioisotope — in tumor tissue, this modality can deliver substantial doses of radiation to the tumors while minimizing exposure of normal tissue. In addition, RIT is able to target multiple metastases throughout the body in a single treatment (Figure 1). Excellent results have been reported using RIT in advanced hematologic malignancies. Single or multiple non-myeloablative doses or high-dose RIT with bone marrow transplantation have produced remarkable results in advanced-stage non-Hodgkin’s lymphoma (NHL) patients whose disease had recurred after standard treatment. Long-term complete remission (CR) following high-dose RIT has been common.
Success in solid tumors has been more limited. However, in several cancers useful progress has occurred. Clinical trials using 131I on either the murine or chimeric antibody L6 yielded responses in approximately half of the patients with advanced, chemotherapy-refractory breast cancer who were tested [4]. Similar antitumor responses have been reported in breast cancer using yttrium-90 (90Y) linked to antibodies reactive with epithelial mucin or carcinoembryonic antigen (CEA) 5, 6•, 7•, 8•. Trials of intraperitoneal RIT therapy as part of combination therapy for ovarian cancer have shown extended remissions and effects on survival 9•, 10•. Here, we present an overview of the current status of RIT and recent results that demonstrate the most useful therapeutic index and/or clinical effects of RIT.
Section snippets
RIT in lymphoma and leukemia
In over 500 patients, NHL has proven exquisitely responsive to RIT using a variety of MoAbs and radionuclides. Advantages of RIT in NHL include the accessibility of the malignant lymphocytes to the vascular system, the presence of abundant high-density surface antigens with expression restricted to lymphocytes and the radiosensitivity of NHL. About the time that anti-idiotypic immunotherapy was reported, DeNardo et al. 11, 12 published the original description of 131I–Lym-1 RIT for patients
RIT advances for multimodality therapy of leukemia
HuM195, a humanized MoAb reactive with the cell surface antigen CD33, specifically targets myeloid leukemia cells [24]. 131I–anti-CD33 conjugates can eliminate large leukemic burdens in patients and have been combined safely with busulfan and cyclophosphamide in 30 patients to eliminate disease before bone marrow transplantation [25]. 90Y–HuM195m is currently under study [26•]. Twelve patients with acute myelogenous leukemia received 0.1–0.3 mCi/kg of 90Y–HuM195 as a singe therapy dose and 111
Ground-breaking work using α particles for RIT
To increase the antileukemic effect of HuM195, 213Bi was conjugated to it. 213Bi emits an 8 MeV α particle and has a half-life of 46 minutes. Eighteen patients with relapsed/refractory acute myelogeneous leukemia or chronic myelomonocytic leukemia were treated with 213Bi–HuM195 [27••]. No acute toxicity has been observed. Delayed non-hematologic toxicity has been limited to transient, low-grade liver function abnormalities. The calculated absorbed dose ratios (comparing organs with leukemic
Breast cancer
RIT has been less effective for solid tumors, in part, because they are less radiosensitive. However, radiosensitivity of breast cancer has been demonstrated in patients with early-stage disease: conservative surgery followed by external-beam radiation therapy to microscopic residual disease in the breast produces the same local disease-free status and overall survival rates for 8–10 years as does modified radical mastectomy 30, 31, 32, 33. To deliver therapy to widespread tumors at levels
Ovarian cancer
Like several other adenocarcinomas, the prognosis for ovarian cancer patients is poor. Five-year survival rates for patients who have responded well to the standard treatments, which consists of cytoreductive surgery and chemotherapy, are only 20–40%. 90Y-labeled murine IgG1 MoAb HMFG1 (Theragyn®, Antisoma PLC, London, UK) reacts with an epithelial mucin, a product of the MUC-1 gene, that is expressed at high levels in an abnormally glycosylated form on the cell surface of over 90% of ovarian
Combined agents for synergy in ovarian cancer therapy
The anti-TAG-72 antibody, CC49, was radiolabeled with 177Lu (a radiometal with β emissions similar to 131I) and given via intraperitoneal administration as a single agent or with human recombinant interferon-α (subcutaneous) with or without paclitaxel (Taxol) [9•]. Eligible patients had TAG-72-expressing tumor limited to the abdominal cavity after surgery/chemotherapy. Radiation dose ratios of 58–139:1 (comparing tumor : bone-marrow) were obtained. Three patients (out of 27) with small-volume
Progress in treating various cancers using RIT
Radiolabeled anti-CEA MoAbs have shown excellent targeting in patients with CEA-producing cancers, such as colorectal, pancreatic, ovarian, breast and medullary thyroid cancers 37, 38, 39, 40. Currently, high-dose myeloablative RIT utilizing a humanized 90Y–MN-14 anti-CEA MoAb (90Y–hMN-14 or CEA-Cide™, Immunomedics Incorporated, Morris Plains, New Jersey) is under study in combination with chemotherapy and followed by PBSC support for treatment of relapsed/refractory CEA-producing cancers (M
Engineered antibody systems
Experience with conventional RIT has suggested that higher doses of radioactivity are associated with a better response rate. However, the doses of radiation required to achieve the highest response rates have required bone marrow or PBSC support 6•, 7•, 8•, 16. Pretargeting RIT represents an alternative to conventional RIT that may enable delivery of higher doses of radiation without concomitant myelosuppression (Figure 3) [43••]. One approach encompasses a three-step delivery system
Conclusions
Immunotherapy and RIT have ushered in a new era in the treatment of cancer. The therapeutic index that can presently be achieved by RIT provides a tool for new combined-modality therapy for many cancers. As the field of antibody engineering comes of age, formerly theoretical questions regarding optimized pretargeting molecules and the most effective linkages for radionuclides take on practical relevance 47, 48. The ability to generate new constructs, such as bivalent antibodies or fusion
Acknowledgements
Colleagues from industry and other institutions have generously provided current information even occasionally when not yet in detailed publication. The authors’ work was supported in part by grant number PHS CA-47829 from the National Cancer Institute, Bethesda.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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