Current Status of Monoclonal Antibodies for Imaging and Therapy of Prostate Cancer

Introduction

Development of hybridoma technology in 1975 (1) was an important breakthrough subsequently honored by the Nobel Prize. While monoclonal antibody (mAb) technology has already revolutionized the field of immunoassays and in vitro diagnostics--serum PSA being but one example--the promise of mAbs in the area of in vivo imaging and therapy has yet to be realized. Nevertheless, because of their theoretical ability to specifically target cytotoxic agents to tumor sites, while sparing normal tissues, mAbs are undergoing active investigation in many tumor types. While early results fell short of high expectations, there has been steady progress in this area and recent developments are encouraging. Just a few examples of this recent progress follow. Trail et al (2) recently published in Science a treatment study of human lung, colon and breast carcinoma xenografts in athymic mice and rats using doxorubicin-conjugated mAb BR96 directed at an antigen closely related to Lewis Y. While the appropriate control treatments demonstrated little or no activity, the authors were able to demonstrate cures of mice with established cancers, cures of mice with extensively disseminated cancers, and cures in a xenograft-bearing athymic rat model where some normal tissues also express the targetted antigen. The latter setting mimicks the typical situation in humans where the target antigen may be expessed by some normal tissues in addition to the cancer.

Our own radiolabelled mAb trials in patients with renal cancer (3) have demonstrated our ability to specifically deliver mAb G250 to tumor sites with peak ratios of tumor:serum of 178:1, tumor:normal kidney of 185:1 and tumor:liver of 92:1. We were able to successfully image all 12 patients in the study whose tumors expressed the G250 antigen (Fig.1). In 3 of the 12 patients, we were able image, and subsequently document pathologically, sites of disease not suspected on conventional studies such as CT, MRI or bone scan. Scanning and autoradiography of the resected specimens demonstrate intense uptake discretely limited to the area of tumor while sparing the adjacent normal tissue (Figs. 2 and 3). A phase I therapy trial with this mAb is ongoing.

Similarly, Kaminski et al, in the New England Journal of Medicine (4), have reported initial results of a trial of ¹³¹I-mAb B1, directed at the CD20 antigen, in patients with non-Hodgkin's lymphoma. These patients had each previously failed a mean of 2.7 chemotherapy regimens. Of 9 patients evaluable for response and toxicity, 4 had complete (CR) and 2 had partial responses (PR). Of the CRs, one lasted 8 months and the remaining were on-going at 8-11 months. Furthermore, some of the responses occurred in the face of bulky disease. Toxicity was minimal.

Lastly, the attributes and strengths of mAbs are particularly well-suited to the demands of prostate cancer imaging and therapy:

1. mAbs can specifically and precisely target tumor sites while sparing normal tissues. The ability to spare normal tissue and the resulting toxicity is particularly important in this generally elderly population.
2. One can link diagnostic or therapeutic radioisotopes to mAbs.
3. Prostate cancer is a relatively radiosensitive target.
4. Prostate cancer metastases predominately involve the bone marrow and lymph nodes--sites which receive very high levels of administered antibody.
5. Individual tumor sites tend to be small volume sites, ideally suited for both antibody delivery and access, as well as for beta-particle cytotoxicity.
6. ⁸⁹Sr therapy, which is only indirectly targetted to prostate cancer metastatic sites, has been shown to provide clinical relief of pain and decrease PSA.
7. The availability of clinical parameters such as PSA and pathological features of a patient's cancer such as stage, Gleason score, extracapsular, seminal vesicle or perineural invasion, positive margins, etc, provides the clinician with appropriate indications for mAb imaging and/or therapy in an adjuvant setting where such therapy is likely to be of the greatest benefit.

Given the theoretical advantages of mAbs in this disease, it is compelling to evaluate this approach.