Radioimmunodetection and therapy of breast cancer

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Breast cancer is the second most-common cause of cancer death in women in the United States. Although more than 60% of patients can now be cured by initial treatment, the rest, although perhaps receiving palliation with currently available therapy, will die of their disease. Early detection of micrometastasis and improved treatment strategies are needed. Monoclonal antibody (mAb)-based imaging and tumor targeted therapy holds the potential to impact these problems. The most significant results of systemically administered antibody-based radiopharmaceuticals for detection and targeted therapy (radioimmunotherapy [RIT]) of breast cancer give strong evidence that this potential can be realized. Interest in immunoimaging recently has focused on small mAb modules used with 18F, 64Cu, or 124I to detect minimal disease in breast cancer by positron emission tomography or single-photon emission computed tomography. Reported therapy trials in advanced breast cancer have yielded objective responses and minimal toxicity. These studies have spanned several radionuclides as well as several mAb, fragments and approaches, including dose intensification with bone marrow support; combined therapy with other modalities (ie, CM-RIT); biodegradable peptide linkers; and pretargeting. RIT evaluated in clinical breast cancer trials has delivered as much as 4000 cGy to metastatic breast cancer per therapy dose with marrow stem cell support. Preclinical studies have demonstrated further promising strategies for breast cancer. RIT studies must address the key issue: enhancing the therapeutic index (tumor effect verses most sensitive normal tissue (bone marrow) effect). Approaches now include newly engineered mAb, scFv modular constructs, blood clearance on demand, enhanced pretargeting, applications of both alpha and beta emitting radionuclides, and combination therapy using molecular triggers for therapeutic synergy. These strategies for detection and treatment of metastatic breast cancer should lead to notable clinical impact on management and cure of breast cancer.

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Molecular targets for imaging and targeted therapy of breast cancer

Theoretically, an ideal target for radionuclide detection and therapy of metastatic breast cancer would be tumor-specific, generously expressed on all the breast cancer cells breast cancer patients, and not released into the circulation. Further useful characteristics of the antigen target include mAb-target interactions that trigger responses sensitizing tumor cells to radiation. Although, perhaps, the ideal tumor-specific targets for imaging or RIT have yet to be found, excellent and useful

Acute and subacute toxicity

Mild-to-moderate clinical toxicity has been anticipated and reported when biologically active monoclonal antibodies or immune targeting molecules combined with or without other biologic response modifiers, (ie, IL-2, IL-6, tumor necrosis factor) are used as part of the radioimmunotherapy.48, 49 It is not surprising that activation of complement, the triggering of normal immune effector cell response, and/or stimulation of other inflammatory mechanisms can cause clinical symptoms. In these

Human Anti-Monoclonal Antibodies (HAMAs)

After exposure to antibodies containing murine proteins, patients may develop HAMAs. A HAMA response usually results in rapid clearance of the therapeutic antibodies for the circulation, thereby reducing tumor uptake. Considerable variability exists in the development of a HAMA response among patients.49 Imaging with very small amounts of antibody (1–2 mg), or smaller constructs, seldom elicits HAMA. Chimeric and humanized MoAb in moderate doses also have less HAMA response. HAMA develops in

Synergy studies

Novel, synergistic, multimodality therapy is needed for breast cancer to combat the molecular mechanisms, genetic mutations and epigenetic abnormalities that protect the cancer from therapeutic interventions. Studies combining chemotherapy and RIT are in progress with various agents. Work with the aggressive human breast cancer model HBT3477 and paclitaxel exemplifies the need of combined breast cancer RIT to overcome such cancer cell mechanisms, ie, mutant nonfunctional p53 and high BCL-2

Summary

Immunoimaging and tumor immunotargeted radionuclide therapy are promising approaches for early detection and CM-RIT treatment of metastatic breast cancer. Because of selective biologic concentration of the antibody and thus the isotope in tumor tissue, this modality can deliver substantial doses of radiation to the tumors while minimizing concomitant exposure of normal tissue and target metastases throughout the body in a single treatment. Although excellent results have been reported using RIT

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    Supported by NCI grants PO1-CA-47,829(UCD), Department of Defense Grant DAMD17 to 01-0177, and Department of Energy Grant DE-FG01 to 00NE22944.

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