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Status of Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy of Cancer

Status of Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy of Cancer

Almost exactly one decade ago, in an editorial published in the New England Journal of Medicine [1], I noted that "progress is slow but sure" in the development of monoclonal antibodies for clinical use. At that time, only muromonab-CD3 (Orthoclone OKT3) was approved for human use to prevent rejection of kidney transplants. In the ensuing 10 years, only one oncologic monoclonal antibody product, satumomoab pendetide (OncoScint CR/OV, Cytogen, Princeton, New Jersey) [2] has been approved by the FDA. Progress surely has been slow.

A Break in the Log-Jam?

What an oncologist wants to know is, has the log-jam been broken? or, said another way, will any of these products be available for me to evaluate in my patients? The answer is a conservative maybe. In the last year, the FDA has presented two oncology imaging products to advisory committees: Verluma (NR-LU-10, NeoRx, Seattle, Washington) [3] for imaging extensive small-cell carcinoma of the lung, and CEA-Scan (arcitumonab, Immunomedics, Morris Plains, New Jersey) [4] for imaging cancer of the colon or rectum. Both of these antibodies have been recommended for approval. Divgi's article discusses the clinical results with OncoScint and CEA-Scan, but doesn't describe the results of the Verluma studies.

Several factors noted by Divgi deserve emphasis. OncoScint (an indium-111-labeled intact anti-TAG72 immunoglobulin G [IgG]) was approved for one-time extrahepatic imaging of presurgical patients with colorectal or ovarian cancer. It appears that these two restrictions have limited the use of OncoScint in the clinic. Recently, based on data presented by Cytogen, the FDA has decided to allow OncoScint to be used multiple times, but the restriction to extrahepatic imaging has been retained. By contrast, CEA-Scan (a technetium-99m-labeled anticarcinoembryonic antigen [CEA] Fab' fragment), appears to be useful in the liver. Although CEA-Scan is superior to CT in extrahepatic areas, it is equivalent and complementary to CT in the liver (ie, CT detects some liver metastases missed by CEA-Scan and CEA-Scan detects disease missed by CT). Furthermore, unlike OncoScint, CEA-Scan appears to be initially nonimmunogenic (< 1% induction of human anti-mouse antibodies [HAMAs], as measured in an antifragment HAMA assay).

Although the published information is sparse, data presented by NeoRx at the FDA's Oncologic Drugs Advisory Committee meeting in December 1995 suggest that Verluma was sensitive for the detection of extensive small-cell carcinoma of the lung in an 89-patient trial (not controlled by surgical confirmation of the imaging results). (By contrast, both OncoScint and CEA-Scan were used in more than 200 patients in whom surgical confirmation was performed.)

After Verluma and CEA-Scan, what are likely to be the next radiolabeled antibodies available for diagnostic use in the clinic? Phase III trials with ProstaScint for prostate cancer and CEA-Scan for non-small-cell lung cancer are underway. Phase III studies of the human antibody, 88BV59H21-2, for colorectal cancer also are ongoing, as are studies employing intraoperative probes with many of the antibodies discussed in the article (iodine-125-labeled CC49, as noted by Divgi, as well as several technetium-99m-labeled antibodies).

Even Slower Progress With Therapeutic Use

As slow as progress has been in diagnostics, progress with therapeutic use of radiolabeled monoclonal antibodies in oncology has been even slower. As Divgi correctly points out, nonmurine antibodies conjugated with cytotoxic isotopes other than iodine-131 are desirable. To date, the therapeutic use of murine monoclonal antibodies has been limited by immunogenicity and bone marrow toxicity. Only in patients with hematologic malignancies have useful antitumor effects been seen regularly. The ideal candidate agent for solid tumor therapy has yet to be convincingly defined. Theoretically, a humanized IgG or F(ab')2, labeled with a strong beta-emitting radioisotope, should offer the best chance for success.

In the realm of nonradiolabeled monoclonal antibodies, other strategies need to be evaluated more extensively. For example, a phase III trial of a humanized anti-HER2 antibody is underway in patients with breast cancer. Also, promising studies are progressing with various strategies for pretargeting nontoxic antibodies to the tumor site to avoid systemic toxicity when the cytotoxic agent is administered.

Summary

In summary, it is clear that the use of radiolabeled murine monoclonal antibodies for radioimmunodetection may soon be regularly employed in oncologic practice. Radioimmunotherapy, on the other hand, is still far from established in clinical practice.

References

1. Pinsky C: Monoclonal antibodies: Progress is slow but sure. N Engl J Med 315:704-705, 1986.

2. Collier B, Abdel-Nabi H, Doerr R, et al: Immunoscintigraphy performed with In-111-labeled CYT-103 in the management of colorectal cancer: Comparison with CT. Radiology 185: 179-186, 1992.

3. Breitz H, Sullivan K, Help W: Imaging lung cancer with radiolabeled antibodies. Semin Nucl Med 23:127-132, 1993.

4. Moffat F, Pinsky C, Hammershaimb L, et al: Clinical utility of external immunoscintography with the IMMU-4 99mTc-Fab antibody fragment (CEA-Scan; arcitumoMoAb) in patients undergoing surgery for carcinoma of the colon and rectum. J Clin Oncol vol 14, 1996 (in press).

 
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