Radioimmunotherapy (RIT) using radiolabeled anti-CD20 monoclonal antibodies (Ab) induces remissions in 50-90% of relapsed lymphoma (NHL) patients; however, most patients eventually succumb to recurrent lymphoma. Our group has documented the promise of radiolabeled anti-CD45 monoclonal Abs administered in the setting of allogeneic stem cell transplantation (SCT) for acute myeloid leukemia (AML), but toxicity remains high and cure rates are still only 60-65% for patients with newly diagnosed AML transplanted in first complete remission (CR) and 20-30% for relapsed AML using directly radiolabeled anti-CD45 Ab and SCT. The efficacy of RIT is currently limited by non-specific delivery of radiation to normal tissues, as a result of the long circulating half-life of radiolabeled antibodies in the bloodstream. The primary objective of this proposal is to launch an academic research career developing innovative approaches to optimize the efficacy of RIT using a two-step streptavidin(SA)-biotin pretargeting strategy to target the anti-CD20 and anti-CD45 antigens on the surface of NHL and AML tumor cells, respectively.
In Aim 1, we will compare and contrast the pharmacokinetics, tumor localization, and therapeutic efficacies obtained with directly radiolabeled anti-CD20 Ab (1F5) and pretargeted RIT using an anti-CD20 tetravalent single chain (scFv)4SA fusion protein followed by escalating doses of radiolabeled DOTA-biotin in murine lymphoma xenograft and disseminated lymphoma transplant models. In dim 2, we will compare the pharmacokinetics, tumor localization, and therapeutic efficacies of leukemia bearing mice treated with radiolabeled anti-human (h)CD45 Ab using conventional RIT, and optimized two-step pretargeting KIT utilizing non-radiolabeled anti-hCD45 (scFv)4SA followed by 90y-DOTA-biotin.
In Aim 3, we will assess the toxicities of anti-CD45 pretargeting in a murine syngeneic leukemia model in which the target antigen is present on both leukemia cells as well as normal hematopoietic tissues.
In Aim 4, we will conduct a phase I clinical study to investigate the feasibility, tolerability, and potential efficacy of pretargeted KIT for patients with relapsed indolent NHL or mantle cell NHL. We hypothesize that targeting radiation specifically to malignant cells using anti-CD20 (scFv)4SA and anti-CD45 (scFv)4SA fusion proteins will augment the efficacy and decrease the toxicity of therapy compared with conventional RIT regimens employing directly radiolabeled Abs. We anticipate that these interventions will ultimately enhance the prognosis for patients with relapsed lymphomas and advanced AML by increasing the response and survival rates, while simultaneously minimizing toxicities.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA095448-03
Application #
7109271
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2004-09-10
Project End
2009-08-31
Budget Start
2006-09-06
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$133,650
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Orozco, Johnnie J; Zeller, Jill; Pagel, John M (2012) Radiolabeled antibodies directed at CD45 for conditioning prior to allogeneic transplantation in acute myeloid leukemia and myelodysplastic syndrome. Ther Adv Hematol 3:5-16
Pagel, John M; Kenoyer, Aimee L; Bäck, Tom et al. (2011) Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model. Blood 118:703-11
Walter, Roland B; Gooley, Ted A; Wood, Brent L et al. (2011) Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 29:1190-7
Shenoi, Jaideep; Gopal, Ajay K; Press, Oliver W et al. (2010) Recent advances in novel radioimmunotherapeutic approaches for allogeneic hematopoietic cell transplantation. Curr Opin Oncol 22:143-9
Walter, Roland B; Press, Oliver W; Pagel, John M (2010) Pretargeted radioimmunotherapy for hematologic and other malignancies. Cancer Biother Radiopharm 25:125-42
Gopal, Ajay K; Press, Oliver W; Shustov, Andrei R et al. (2010) Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma 51:1523-9
Walter, R B; Pagel, J M; Gooley, T A et al. (2010) Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 24:1276-82
Wilbur, D Scott; Park, Steven I; Chyan, Ming-Kuan et al. (2010) Design and synthesis of bis-biotin-containing reagents for applications utilizing monoclonal antibody-based pretargeting systems with streptavidin mutants. Bioconjug Chem 21:1225-38
Pagel, John M; Orgun, Nural; Hamlin, Donald K et al. (2009) A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations. Blood 113:4903-13
Pagel, John M; Matthews, Dana C; Kenoyer, Aimee et al. (2009) Pretargeted radioimmunotherapy using anti-CD45 monoclonal antibodies to deliver radiation to murine hematolymphoid tissues and human myeloid leukemia. Cancer Res 69:185-92

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