Christopher C. Badger

Radiolabeled-Antibody Therapy of B-Cell Lymphoma with Autologous Bone Marrow Support

BACKGROUND Radiolabeled monoclonal antibodies recognizing B-lymphocyte surface antigens represent a potentially effective new therapy for lymphomas. We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse. METHODS Sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 mg per kilogram of body weight) trace-labeled with 5 to 10 mCi of 131I. The doses of radiation absorbed by tumors and normal organs were estimated by serial gamma-camera imaging and tumor biopsies. Patients whose tumors were estimated to receive greater doses of radiation than the liver, lungs, or kidneys (i.e., patients with a favorable biodistribution) were eligible for therapeutic infusion of 131I-labeled antibodies according to a phase 1 dose-escalation protocol. RESULTS Twenty-four patients had a favorable biodistribution, and 19 received therapeutic infusions of 234 to 777 mCi of 131I-labeled antibodies (58 to 1168 mg) followed by autologous marrow reinfusion, resulting in complete remission in 16, a partial response in 2, and a minor response (25 to 50 percent regression of tumor) in 1. Nine patients have remained in continuous complete remission for 3 to 53 months. Toxic effects included myelosuppression, nausea, infections, and two episodes of cardiopulmonary toxicity, and were moderate in patients treated with doses of 131I-labeled antibodies that delivered less than 27.25 Gy to normal organs. CONCLUSIONS High-dose radioimmunotherapy with 131I-labeled antibodies is associated with a high response rate in patients with B-cell lymphoma in whom antibody biodistribution is favorable.

Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody.

The biodistribution, toxicity, and therapeutic potential of anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 (131I) was evaluated in ten patients with advanced-, low- or intermediate-grade non-Hodgkins lymphomas who failed conventional treatment. Sequential dosimetric studies were performed with escalating amounts of antibody MB-1 (0.5, 2.5, 10 mg/kg) trace-labeled with 5 to 10 mCi 131I. Serial tumor biopsies and gamma camera imaging showed that the 10 mg/kg MoAb dose yielded the best MoAb biodistribution in the ten patients studied. Biodistribution studies in the five patients with splenomegaly and tumor burdens greater than 1 kg indicated that not all tumor sites would receive more radiation than normal organs, and these patients were therefore not treated with high-dose radioimmunotherapy. The other five patients did not have splenomegaly and had tumor burdens less than 0.5 kg; all five patients in this group showed preferential localization and retention of MoAb at tumor sites. Four of these patients have been treated with 131I (232 to 608 mCi) conjugated to anti-CD37 MoAb MB-1, delivering 850 to 4,260 Gy to tumor sites. Each of these four patients attained a complete tumor remission (lasting 4, 6, 11+, and 8+ months). A fifth patient, whose tumor did not express the CD37 antigen, was treated with 131I-labeled anti-CD20 MoAb 1F5 and achieved a partial response. Myelosuppression occurred 3 to 5 weeks after treatment in all cases, but there were no other significant acute toxicities. Normal B cells were transiently depleted from the bloodstream, but immunoglobulin (Ig) levels were not affected, and no serious infections occurred. Two patients required reinfusion of previously stored autologous, purged bone marrow. Two patients developed asymptomatic hypothyroidism 1 year after therapy. The tolerable toxicity and encouraging efficacy warrant further dose escalation in this phase I trial.

A mouse model for calculating cross-organ beta doses from yttrium-90-labeled immunoconjugates

Background. The organs of laboratory mice used in radioimmunotherapy experiments are relatively small compared to the ranges of high‐energy yttrium‐90 (Y‐90) beta particles. Current Medical Internal Radiation Dose (MIRD) dosimetry methods do not account for beta energy that escapes an organ. A dosimetry model was developed to provide more realistic dose estimates for organs in mice who received Y‐90‐labeled antibodies by accounting for physical and geometric factors, loss of beta dose due to small organ sizes, and cross‐organ doses.

Allogeneic marrow transplantation for acute leukemia in relapse

The results of allogeneic marrow transplantation in 75 patients with acute lymphoblastic leukemia and 63 patients with acute non-lymphoblastic leukemia in relapse are reviewed. The effects of various chemotherapeutic regimens added to the basic regimen of cyclophosphamide (Cy) 60 mg/kg given on each of two successive days followed by 1000 rad of total body irradiation (TBI) were evaluated. The regimens tested were dimethylbusulphan (DMB), 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) and daunorubicin. Seventeen of 138 patients are alive between three and nine and a half years from transplantation. The addition of other chemotherapeutic agents to th basic Cy and TBI regimen did not decrease relapse frequency or prolong survival.

In vitro measurement of avidity of radioiodinated antibodies

A determination of the ability of radiolabeled antibodies to bind to their target antigen is an essential step in the initial selection of antibodies for clinical use as well as a quality control measure. In our studies of the 131I-labeled anti-Thy 1.1 antibody treatment of murine lymphoma we have used cell binding assays with a combination of Lineweaver-Burk analysis to determine immunoreactivity and Scatchard analysis to determine antibody avidity. Both assays were systematically influenced by target cell fixation and measurement of avidity was dependent on immunoreactivity. For 131I-labeled anti-Thy 1.1 antibody, avidity was a much more sensitive indicator of iodination damage and predictor of in vivo behavior than was immunoreactivity, while for other antibodies immunoreactivity has been a better indicator of labeling damage. Thus, immunoreactivity and avidity assays are complementary and knowledge of both factors is required for the design of sensitive quality control procedures for radiolabeled antibodies.

Synthesis and radioiodinationof tyramine cellobiose for labeling monoclonal antibodies

A tyramine cellobiose (TCB) adduct was synthesized by the reductive amination of cellobiose by tyramine with a product yield of 78%. The TCB adduct was purified by chromatography and then iodinated using the chloramine-T method. After iodination, the adduct was activated with cyanuric chloride and linked to protein by incubation at room temperature for 2 h. Immunoreactivity and avidity were well maintained compared to electrophilically radioiodinated 1A14 whole antibody. The tumor uptake and retention were strikingly greater with iodinated TCB-antibody compared to that of the conventionally iodinated antibody; whereas, the plasma clearance curve and uptake in other organs were not changed. This method of labeling increases the retention time of radioiodine in tumors and thus extends to iodinated antibodies one of the advantages of indium labels, namely that the isotope is not readily washed out of the tumor after it becomes localized.

Prospects for monoclonal antibody therapy of leukemia and lymphoma

The development of monoclonal antibodies has led to renewed interest in the use of antibodies to treat malignant disease. Unfortunately, treatment with unmodified antibodies has been disappointing. Therapy with unmodified antibodies has been limited by the failure of host effector mechanisms to eliminate antibody‐coated tumor cells and by the emergence of variant cells lacking the target antigen. The use of antibodies as carriers of radionuclides has the potential for overcoming both these limitations because the conjugates will be directly cytotoxic and a conjugate bound to a cell surface will deliver radiation to adjacent cells lacking the target antigen. Experimental and clinical therapy trials of radionuclide antibody conjugates have yielded promising results with both tumor‐specific antibody and with antibodies against differentiation antigens. Bone marrow toxicity has been dose limiting. Bone marrow support will most likely be required for the treatment of leukemia and lymphoma due to the marrow involvement with malignant cells. In the case of solid tumors, bone marrow infusion may allow administration of curative doses of radionuclide conjugates. Although at an early stage in development, radiolabeled antibodies have the potential for contributing significantly to the therapy of malignant disease. Cancer 58:584‐589, 1986.

Radiolabeled antibody therapy of human B cell lymphomas.

Modern chemotherapy regimens are capable of curing the majority of patients with newly diagnosed diffuse aggressive lymphomas1, but few patients with low-grade lymphomas or relapsed aggressive lymphomas can be cured with conventional therapy. High dose chemoradiotherapy in conjunction with marrow transplantation affords long term disease-free survival for approximately 25% of such patients2,3, but toxicity is formidable and post-transplant relapse and treatment-related complications result in the death of most such patients. Targeted radiotherapy using radiolabeled antibodies (RAb) offers a potentially effective new approach for refractory malignancies as demonstrated by a variety of animal and human studies4–13. In this report we summarize our experience administering radiolabeled anti-B cell antibodies to patients with refractory non-Hodgkin’s lymphomas in a phase I dose escalation trial.

Localized beta dosimetry of 131I-labeled antibodies in follicular lymphoma.

The purpose of this study is to assess the multicellular dosimetry of 131I-labeled antibody in follicular lymphoma based on histological measurements on human tumor biopsy tissue. Photomicrographs of lymph node specimens were analyzed by first-order treatment to determine the mean values and statistical variations of the radii of follicles (260 +/- 90 microns), interfollicular distances (740 +/- 160 microns), and the number density of follicles [60 +/- 18 in a volume of (2 X 1480 microns)3]. Based on these measurements, two geometrical models were developed for localized beta dosimetry. The first, a regular cubic lattice model, assumes no variation in follicular radius of follicles and interfollicular distance. The second, a randomized distribution model, is a more complicated but more realistic representation of observed histological specimens. In this model, Monte Carlo methods were used to reconstruct the spatial distribution of follicles by simulating the distribution of the radii of follicles, interfollicular distances, and the number density of follicles. Dose calculations were performed using Bergers point kernels for absorbed-dose distribution for beta particles in water, assuming the 131I-labeled antibodies as point sources. It was assumed that the activity concentration of the labeled antibody within the follicles was ten times the activity concentration in the interfollicular spaces. The spatial distribution of localized dose was calculated for a tumor having an average dose of 40 Gy. The localized dose was found to be highly nonuniform, ranging from 20 to 90 Gy, and varying by a factor of about 2 from the average tumor dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiolabeled antibody therapy of lymphoma

Impressive improvements have occurred over the past 20 years in the development of curative therapies for patients with newly presenting intermediate and high grade lymphomas, as documented in the preceding chapters. However, patients with low grade lymphomas or relapsed non-Hodgin’s lymphomas of any grade are rarely cured with conventional doses of chemotherapy and radiation therapy. High-dose chemoradiotherapy in conjunction with bone marrow transplantation is capable of producing long-term disease-free survival in 20–50% of such patients [1, 2] but is associated with a 10–15% chance of treatment-related mortality. Development of novel new treatment approaches with higher cure rates and less toxicity, therefore, remains a high priority in the field of oncology.