A new era for radiolabeled antibodies in cancer?

doi:10.1016/S0952-7915(99)00017-5

Current Opinion in Immunology

Volume 11, Issue 5, 1 October 1999, Pages 563-569

https://doi.org/10.1016/S0952-7915(99)00017-5 Get rights and content

Abstract

Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3–50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy.

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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Maximum tolerated dose, toxicity, and efficacy of ¹³¹I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma

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Yttrium-90, produced by irradiating Y₂O₃ (15 mg) in the Pakistan Research Reactor (PARR-I) at a flux of ∼1.5×10¹⁴ neutrons/cm²/s, was used to prepare yttrium-90 hydroxyapatite particles for radiosynovectomy applications. The irradiated material was dissolved in concentrated hydrochloric acid, evaporated and taken up in distilled water. The 120 h irradiation resulted in the production of ∼12 GBq (324 mCi) of ⁹⁰Y at the end of irradiation (EOI) and the corresponding specific activity was ∼1017 GBq/g of yttrium. Hydroxyapatite (HA) particles were synthesized by an already reported method. Labeling of HA particles with ⁹⁰Y was studied without a transchelating agent. Labeling yields of ∼100% could be achieved with 40 mg of HA and 0.4 mg of ⁹⁰Y. In vitro studies showed <2% loss of ⁹⁰Y activity in normal saline and 1% human serum albumin solution over a period of 8 days. The high labeling yield, good stability and ease of preparation of the ⁹⁰Y-HA particles indicate that these particles may find wide application in radiation synovectomy.
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ReviewA new era for radiolabeled antibodies in cancer?

Abstract

Introduction

Section snippets

RIT in lymphoma and leukemia

RIT advances for multimodality therapy of leukemia

Ground-breaking work using α particles for RIT

Breast cancer

Ovarian cancer

Combined agents for synergy in ovarian cancer therapy

Progress in treating various cancers using RIT

Engineered antibody systems

Conclusions

Acknowledgements

References and recommended reading

Semin Nucl Med

Blood

Lancet

Radiother Oncol

Gynecologic Oncology

A revolution in the treatment of non-Hodgkin’s lymphoma

Cancer Biother Radiopharm

The development of monoclonal antibodies for the therapy of cancer

Crit Rev Eukaryotic Gene Expr

Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody

Anticancer Res

Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: results of a phase I clinical trial

J Nucl Med

Phase I study of high-dose radioimmunotherapy with 90-Y-hu-BrE-3 followed by autologous stem cell support (ASCS) in patients with metastatic breast cancer [abstract]

Cancer Biother Radiopharm

Initial results of a phase I trial evaluating 90yttrium (90Y)-chimeric T84.66 (cT84.66) anti-CEA antibody and autologous stem cell support in CEA-producing metastatic breast cancer [abstract]

Cancer Biother Radiopharm

Dosimetry-based therapy in metastatic breast cancer patients using 90Y Mab 170H.82 with autologous stem cell support and cyclosporin A

Clin Cancer Res

Intraperitoneal radioimmunotherapy for refractory epithelial ovarian cancer with 177Lu-CC49

Minerva Biotechnologica

Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis

Oncology Rep

Treatment of a patient with B cell lymphoma by I-131 Lym-1 monoclonal antibodies

Int J Biol Markers

Treatment of B cell malignancies with I-131 Lym-1 monoclonal antibodies

Int J Cancer

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma

J Clin Oncol

Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma

Clin Cancer Res

Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support

N Engl J Med

Iodine-131 Anti-B1 antibody for non-Hodgkin’s lymphoma (NHL): overall clinical trial experience [abstract]

Proc Am Soc Clin Oncol

I-131 anti-B1 antibody for previously untreated follicular lymphoma (FL): clinical and molecular remissions [abstract]

Proc Am Soc Clin Oncol

Pharmacokinetics, dosimetry and initial therapeutic results with 131I- and 111In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody (MAb) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL)

Clin Cancer Res

Low-dose fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody

Cancer Biother Radiopharm

Maximum tolerated dose, toxicity, and efficacy of 131I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma

J Clin Oncol

Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL)

Cancer

Humanized monoclonal anti-CD33 antibody HuM195 in the treatment of relapsed/refractory acute myelogenous leukemia (AML): preliminary report of a phase II study [abstract]

Proc Am Soc Clin Oncol

Review
A new era for radiolabeled antibodies in cancer?

Initial results of a phase I trial evaluating ⁹⁰yttrium (⁹⁰Y)-chimeric T84.66 (cT84.66) anti-CEA antibody and autologous stem cell support in CEA-producing metastatic breast cancer [abstract]

Dosimetry-based therapy in metastatic breast cancer patients using ⁹⁰Y Mab 170H.82 with autologous stem cell support and cyclosporin A

Pharmacokinetics, dosimetry and initial therapeutic results with ¹³¹I- and ¹¹¹In-/⁹⁰Y-labeled humanized LL2 anti-CD22 monoclonal antibody (MAb) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL)

Low-dose fractionated radioimmunotherapy for B-cell malignancies using ¹³¹I-Lym-1 antibody

Maximum tolerated dose, toxicity, and efficacy of ¹³¹I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma