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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.

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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-Hodgkin's 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.

Concentrations of 5 marker proteins were measured in synovial fluid and serum samples from knee effusions of 11 patients with rheumatoid arthritis and 9 with osteoarthritis. Indirect determinations of synovial plasma flow and lymphatic drainage were obtained by measuring iodide clearance (mVminute) and radioalbumin clearance (mYminute). Together with protein concentrations, these determinations allowed us to calculate: 1) the flux of each marker protein through synovial tissues (mghinute); 2) the volume of plasma cleared by synovium per unit time (mlhinute); and 3) the fractional extraction per passage through the synovial microcirculation (protein permeance). These measures differed substantially between rheumatoid arthritis and osteoarthritis patient populations and quantified the severity of the microvascular lesion in rheumatoid synovitis.Synovial microvascular permeability plays an important role in the pathophysiology of synovial effusions. Permeability changes, however, have not been easily quantified. Previous evaluations assayed marker proteins in synovial fluid (SF) and serum (S) and then used the concentration ratio (SF:S) to charFrom the Departments of Medicine and Radiology, University of Washington, Seattle.Supported in part by NIH grants AM-22186, AM-32811, AM-07108, and RR-37, and by a Clinical Research Center grant from the Arthritis Foundation.acterize the "leakiness" of the synovial tissue barrier (1,2). Such studies provided support for the view that rheumatoid synovial tissues are more permeable than are osteoarthritic synovial tissues. The regression lines created by plotting SF:S versus protein molecular size have also been useful in determining whether specific proteins are consumed or synthesized within the articular compartment (1-3).Unfortunately, SF:S protein ratios reflect not only the permeability of synovial microvessels, but also the kinetics of plasma delivery to and lymphatic removal from synovial tissues. The contributions of these kinetic factors must be resolved in order to specifically assess microvascular permeability. In addition, net intraarticular synthesis or catabolism must be considered (4). Since the SF:S ratio fails to distinguish the several factors contributing to protein delivery and removal, it remains an inadequate measure of synovial microvascular permeability (5).Evidence from studies of animals indicates that protein traffic across the synovium is unidirectional, with proteins delivered to articular tissues by the microcirculation and removed by lymphatic drainage (6,7). Three groups of investigators have found that radiolabeled proteins of widely different molecular radius are removed from human articular tissues at identical rates (8-10). A shared rate suggests that proteins are not cleared by diffusion (in which case, the removal of different proteins would be inversely drainage.We have recently introduced a method for deriving the articular clearance of radiolabeled albumin (RISA) from human synovial effusions (11). Be-98195.