LL2 is an internalizing anti-CD22 MAb found to be reactive with virtually all types of non-Hodgkin's lymphoma (NHL). Both animal and clinical studies have demonstrated that 90Y-LL2 results in 2- 3 fold higher tumor-to-organ dose ratios than 131I-LL2 and is therefore expected to be superior for RAIT. Additional advantages of 90Y over 131I include the potential for killing a wider radius of cells, the relative simplicity and safety of antibody conjugation, and administration in the outpatient setting. A humanized form of LL2 (hLL2) has been developed and pilot human studies showed hLL2 to have very similar targeting properties to the murine form. In this renewal application, we intend to continue to utilize 90Y-hLL2 in the treatment of relapsed/refractory NHL, by completing the previously proposed phase I trial with non-myeloablative doses of 90Y-hLL2 without the need of peripheral blood stem cell rescue (PBSCR) in patients with low-grade NHL. This is justified by the results of several clinical trials, which continue to demonstrate the merit of this approach in these patients. However, we will also conduct a newly designed phase I/II trial using myeloablative doses of 90Y- hLL2 in conjunction with PBSCR. Our hypothesis is that we will, by utilizing high dose 90-Y-hLL2 combined with PBSCR, be able to achieve significantly better anti-tumor responses in patients with aggressive NHL (intermediate, high-grade and mantle cell NHL), where non-myeloablative RAIT has had only limited success. We will also utilize this approach to address the need for a treatment option in patients with aggressive NHL, who have failed high-dose chemotherapy with hematopoietic stem cell rescue, and, are left with very limited treatment options. These patients are currently offered the option of non-myeloablative RAIT, which usually only results in partial and transient responses in this group of patients in need for a more aggressive therapy.
