Phase I/II Trial of Multiple Dose¹³¹Iodine-MAb LL2 (CD22) in Patients with Recurrent Non-Hodgkin's Lymphoma

Abstract

The purpose of this to evaluate in a phase I/II study the efficacy and toxicity of a multi-dose administration of 131I labeled CD22 monoclonal antibody (131I-MAb-LL2) in escalating dose cohorts administered to relapsed non-Hodgkin's lymphoma (NHL) patients. Twenty-one patients with relapsed NHL received one of four dose levels of 131-MAb-LL2 administered in a twice weekly pattern. Starting with dose level 2, the patients also received 20 mg of unlabeled LL2 prior to each radiolabeled dose administered. Previously stored autologous peripheral blood progenitors were reinfused in case of prolonged cytopenias. Patients could repeat the same treatment if they had stable disease or a response to the first therapy at 8 weeks, and had not received their peripheral blood progenitors with the first cycle. Combining all of the dose cohorts, there were 5 complete responses or complete responses (undetermined) and 2 partial responses for a total response rate of 7/21 (33%). There was no dose response effect with responses documented at all dose levels. Expected toxicities were hematopoietic, requiring stem cell re-infusion in 5 patients. Other toxicities included hypothyroidism in 3 patients, and human anti-mouse antibody formation (HAMA) in 4 patients. In conclusion, 131I-MAb-LL2, when administered in a multi-dose fashion with 20 mg unlabeled antibody pre-dosing, resulted in a response rate of 33% in heavily pre-treated NHL patients. Non-hematologic toxicities were mild and few in number. Further evaluation of this treatment is warranted and further dose escalation will be possible.

Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin’s Lymphoma

“…Previous studies have evaluated murine and humanized forms of an anti-CD22 antibody both preclinically and clinically, as a carrier of radionuclides for NHL imaging and therapy (42)(43)(44), as well as a conjugate with toxins [ricin (45)(46)(47), pseudomonas exotoxin (48), or RNase (49)] for therapy. Results of these trials with one radioimmunoconjugate form of the antibody (42,43) suggested that the unlabeled Fig. 2 OR rates by dose for evaluable patients with DLBCL.…”

Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

“…The first clinical studies of the LL2 construct were trials evaluating the murine version as a radioimmunoconjugate for tumor imaging (Juweid et al, 1995(Juweid et al, , 1999Behr et al, 2002) or as radioimmunotherapy (Siegel et al, 1991;Kreitman et al, 1993;Behr et al, 1999Behr et al, , 2002Juweid et al, 1999;Linden et al, 1999Linden et al, , 2002Linden et al, , 2005Vose et al, 2000;Goldenberg, 2001Goldenberg, , 2003Postema et al, 2003;Sharkey et al, 2003Chatal et al, 2005;. Other toxin-conjugate forms have been developed and tested only pre-clinically to date, such as those that include Pseudomonas exotoxin (Newton et al, 2001a, b) and amphibian RNase (Leonard et al, 2005a, b;Newton et al, 2001a, b).…”

“…Therapy was well tolerated, with doselimiting toxicity being myelosuppression. Subsequently, the use of 131 I-murine LL2 IgG in a multiple-dosing scheme was reported by Vose et al (2000), and objective responses were noted in 7/21 patients. Humanization of the antibody (into epratuzumab) was then performed to minimize immunogenicity and to optimize its pharmacokinetics, safety and efficacy (Leonard et al, 2003).…”

Outpatient radioimmunotherapy with Bexxar

“…This therapy targets the CD20 antigen present on most B-cell lymphomas and has been shown to be effective against low-grade and transformed low-grade NHL in both nonmyeloablative 3 and myeloablative (followed by autologous stem cell transplant) 4 protocols. Other RITs in development include another anti-CD20 MAb Y2B8 radiolabeled with yttrium-90, 5 Lym-1 (which targets the HLA-DR10 antigen on the surface of malignant B-lymphocytes) radiolabeled with iodine-131, 6 or copper-67 7 and LL2 (which targets the CD22 antigen on B-cell lymphomas) radiolabeled with iodine-131 8 or yttrium-90. 9 Initial RIT treatments were performed on an inpatient basis.…”