Pretargeted Radioimmunotherapy (PRIT™) for Treatment of Non-Hodgkin's Lymphoma (NHL): Initial Phase I/II Study Results

Abstract

Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.

Pretarget radiotherapy with an anti-CD25 antibody-streptavidin fusion protein was effective in therapy of leukemia/lymphoma xenografts

“…Therapeutic studies showed that 70-100% of xenografted mice were cured with 90 Y-DOTA-biotin, and the toxicity was significantly lower when compared with 90 Y directly labeled intact antibodies. Clinical trails also validated the feasibility of the Pretarget approach (19)(20)(21)(22).…”

The conjugate Rituximab/saporin-S6 completely inhibits clonogenic growth of CD20-expressing cells and produces a synergistic toxic effect with Fludarabine

“…9 In addition, a pilot study introducing a novel 'pretargeting' strategy of two-step radioimmunotherapy using streptavidin-labeled anti-CD20 antibodies was recently published. 10 A different way to improve mAbs effects is to conjugate them to a toxic moiety, in order to obtain immunotoxins, chimeric proteins with specific cytotoxic effect. To this purpose, a variety of bacterial and plant toxins have been utilized.…”

Antibody-targeted radiation cancer therapy

“…Obviously, renal toxicity remains a concern when using this strategy. Using this latter motif, a Phase I/II trial was conducted that treated NHL patients with rituximab-SA conjugate injected sequentially, followed by a clearing agent (biotin-N-acetyl-glucosamine) and thereafter with 30 or 50 mCi per m 2 of 90 Y-DOTAbiotin 86 . Patients responded favourably, with only transient haematological toxicities.…”