Chaitanya R. Divgi 
Memorial Sloan-Kettering Cancer Center, New York, NY

Radioimmunotherapy in Solid and Hematologic Neoplasms

The premise underlying radioimmunotherapy in cancer is that preferential accumulation in tumor of a radionuclide-conjugated antibody will permit selective delivery of cytotoxic radioactivity and thus cause tumor regression.

Iodine-131 labeled antibodies have been studied most extensively. High specific activity radioiodinated antibody with intact immunobiologic function, stable for long periods of time, has made possible centralized production of large amounts of 131I labeled antibody. In addition to its potentially cytotoxic beta-minus emission, 131I emits a high-energy gamma radiation that permits external detection. This allows single photon imaging to demonstrate targeting of radioimmunoconjugate to tumor. It also permits quantitation of radioactivity in the body and in serum, allowing calculation of radiation absorbed dose to tumor and normal organs. Iodine is a suboptimal nuclide for conjugation with antibodies that internalize subsequent to interaction with antigen. In most cases, internalization results in dehalogenation of the antigen-antibody complex with release of radioiodine from the cell and a consequent decrease in cytotoxic potential.

The limitations of 131I spurred the study of other radionuclides with therapeutic potential. These may be divided into three major types of cytotoxic agents: pure beta emitters (either electron or positron), such as 67Cu and 90Y; alpha emitters (213Bi, 211At); and beta emitters that emit gamma radiation (131I, 177Lu, 186Re). The list may also be divided into three groups of radiochemicals: halogens (iodine; 211At); metals (90Y, 67Cu, 213Bi); and transitional elements (rhenium).

Yttrium-90 has been, after 131I, the most extensively studied radionuclide in RIT. It has a high-energy beta emission with cytotoxic potential. The first radioimmunoconjugate approved by the Food and Drug Administration for the therapy (Zevalin®) of B-cell lymphoma is a 90Y-labeled IgG. Moreover, radiometal-labeled antibodies are not as susceptible to intracellular degradation and are therefore preferred in internalizing systems.

The rhenium radioisotopes, transitional elements, are increasingly being explored for their potential as cytotoxic agents. Both 186Re and 188Re have been labeled to antibodies, usually through a suitable linker. 186Re has been more extensively studied. Both isotopes emit gamma emissions eminently suitable for imaging with standard gamma cameras. 188Re has a shorter half-life with a more energetic beta-minus emission. The ability to produce 188Re using a tungsten-188 generator system offers the potential of easy availability, while its relatively short (17 hour) half-life will probably limit its use to loco-regional application, or conjugated with antibody fragments or smaller molecules.

Recent developments in radiochemistry have also made possible the clinical study of alpha-emitters labeled to antibodies. Astatine-211 is a halide (T½ 7 hours) that has been stably conjugated to antibodies using a linker (unlike iodine, this halide cannot be directly labeled). At-211 labeled antibodies are being studied in loco-regional radioimmunotherapy trials in patients with malignant intra-cranial neoplasms. Bismuth-213, an alpha-emitter with a much shorter (45 minute) half-life, is being studied in myelogenous leukemias; this radiometal may be conjugated to antibodies using methodology established for other radiometals. Its parent, actinium-225, has a 10-day half-life and emits a cascade of alpha particles, leading to its study as an in vivo “nanogenerator.” The development of alpha-based radioimmunotherapy may be limited to loco-regional therapy and to therapy of hematologic neoplasms, where binding of radioimmunoconjugate to tumor is relatively rapid. Its extremely high energy deposition (LET) may preclude its use in systemic therapy (except perhaps in the adjuvant situation), where irradiation of normal tissue may preclude delivery of adequate cytotoxic radiation to tumor. High LET nuclides also include those that emit Auger electrons upon decay. Iodine-125 is the prototypical nuclide, though its long T½ makes it a less than optimal nuclide for successful therapy. However, Auger electron emission is cytotoxic only when the decay occurs in or near the nucleus, since the high energy deposition occurs over a very short (less than a cell diameter) distance. This limits the use of Auger emitters to use with internalizing antibodies, though the extremely low passive irradiation of normal tissues makes possible the administration of large amounts of radioactivity.

Future directions in radioimmunotherapy.

Dosimetry-based radioimmunotherapy. Studies in B-cell lymphoma, and retrospective evaluation of data from solid tumor RIT trials, demonstrated that radiation absorbed dose to marrow is the most important predictor of toxicity. The development of relatively non-immunogenic antibodies has led to the increasing use of an initial dose of radioimmunoconjugate to measure radiation absorbed dose to determine the amount of radioactivity administered in subsequent RIT. These treatment schema are similar to those used to determine the maximum safe dose of 131I for thyroid carcinoma, and to those currently used in 131I anti-CD20 RIT trials.

Fractionated radioimmunotherapy. The limitations of antigen density, changes over time in tumor interstitial pressure and vascular flow as well as radioantibody specific activity, may necessitate multiple radioimmunotherapy treatments, as with anti-CD33 antibodies. Theoretical models have proposed that while tumor cell survival fraction is less following single large dose RIT, cell repopulation following fractionated RIT may occur at a slower rate.

Constructs. Genetic engineering has made possible the development of antigen-binding proteins with great potential for radioimmunotherapy. Details of antigen-binding constructs are covered elsewhere in this symposium.

Pre- targeting. The relatively low absolute uptake of antibodies in tumor led to the exploration of novel multi-step targeting systems. In essence, the tumor is pre-targeted by an antibody that has a tumor-recognition domain and another that recognizes a fast-clearing ligand that can be suitably radiolabeled, which is administered after a period of time sufficient to allow for tumor targeting as well as systemic clearance of unbound antibody. The rapid targeting of the radioligand to the antibody, as well as its rapid systemic clearance, results in significantly increased relative tumor uptake of radioactivity.

Conclusions.
Monoclonal antibodies offer specificity and low toxicity, making them attractive, when suitably radiolabeled, for the therapy of cancer. Murine antibodies have been studied extensively, and have permitted understanding of constraints and opportunities. A radiolabeled murine antibody has been approved for the therapy of non-Hodgkin’s lymphoma. The next generation of radioimmunotherapy will involve tailored non-immunogenic molecules with optimal clearance, conjugated with nuclides that have suitable characteristics: short path length nuclides for minimal residual or micrometastatic disease, and energetic beta emitters for bulky disease. Multi-step targeting methods will result in higher selective tumor uptake of radioactivity. Genetically engineered constructs will also permit delivery of novel cytotoxic radiation such as alpha emission that will deliver high selective radiation while sparing normal tissue.

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