Preliminary clinical trials have demonstrated that radiolabeled anti-CD20 monoclonal antibodies can achieve remissions in 65-90% of lymphoma patients failing chemotherapy. However, most patients treated with conventional radiolabeled antibodies (RAb) subsequently relapse and die of recurrent lymphoma. The objective of this research proposal is to optimize radioimmunotherapy (RIT) of B cell lymphomas utilizing pretargeting amplification strategies to improve the efficacy and decrease the toxicity of conventional RIT. Two separate pretargeting approaches will be investigated, one using streptavidin (SA) and radioactive biotin and the second employing molecularly engineered bispecific anti-CD20 x anti-ligand antibodies which bind covalently to radiolabeled ligands. First, we will compare the biodistributions, toxicities and efficacies of 4 genetically engineered SA mutant molecules with native SA in combination with either biotin or a synthetic divalent bis-biotin targeting molecule in a mouse lymphoma xenograft model. These streptavidin mutants will afford a unique opportunity to test the effect of SA avidity on tumor penetration as delineated in the ?binding site barrier? hypothesis. Next, we will compare the in vivo biodistribution, radiation dosimetry, and therapeutic efficacy of pretargeted β-emitting radionuclides (90Y, 177Lu) with pretargeted α-emitters (213Bi 211At, 225Ac) in murine xenograft models. Finally, we will evaluate the pharmacokinetics, biodistributions, toxicities and efficacies of novel molecularly designed bispecific anti-CD20 x anti-ligand Abs which possess a molecularly engineered binding pocket capable of binding covalently to synthetic radiolabeled electrophilic ligands. These bispecific anti-CD20 x anti-ligand Abs will be compared directly to the SA-biotin pretargeting approach in lymphoma models. We hypothesize that the pretargeting strategies defined in this proposal will improve the tumor-to-normal organ ratios of absorbed radiation compared with conventional RIT, allowing improvement in response rates and response durations with less toxicity than is currently feasible. We hypothesize that pretargeting will eliminate the necessity of administering myeloablative doses of 131I-anti-CD20 Ab with hematopoietic stem cell rescue to achieve maximal response rates and survival rates. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for human Non- Hodgkin's lymphomas.

Public Health Relevance

/Relevance: Approximately 62,000 Americans are expected to develop Non Hodgkin?s Lymphoma in 2007 and only one third will be cured with conventional treatments. Radiolabeled monoclonal antibodies have recently emerged as a promising new treatment modality that induces remissions in most lymphoma patients, even after failure of standard chemotherapy and radiotherapy. This grant proposal describes the development of several innovations that markedly improve the effectiveness and decrease the toxicity of radiolabeled antibodies targeting the CD20 antigen on human B cell lymphomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Prasanna, Pat G
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Fred Hutchinson Cancer Research Center
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Palanca-Wessels, Maria Corinna; Press, Oliver W (2014) Advances in the treatment of hematologic malignancies using immunoconjugates. Blood 123:2293-301
Green, Damian J; Orgun, Nural N; Jones, Jon C et al. (2014) A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies. Cancer Res 74:1179-89
Procko, Erik; Berguig, Geoffrey Y; Shen, Betty W et al. (2014) A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. Cell 157:1644-56
Gopal, Ajay K; Gooley, Ted A; Rajendran, Joseph G et al. (2014) Myeloablative I-131-tositumomab with escalating doses of fludarabine and autologous hematopoietic transplantation for adults age ? 60 years with B cell lymphoma. Biol Blood Marrow Transplant 20:770-5
Matesan, Manuela; Rajendran, Joseph; Press, Oliver W et al. (2014) 90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution. Nucl Med Commun 35:1132-42
Press, Oliver W; Unger, Joseph M; Rimsza, Lisa M et al. (2013) Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol 31:314-20
Press, Oliver W; Unger, Joseph M; Rimsza, Lisa M et al. (2013) A comparative analysis of prognostic factor models for follicular lymphoma based on a phase III trial of CHOP-rituximab versus CHOP + 131iodine--tositumomab. Clin Cancer Res 19:6624-32
Pagel, John M; Kenoyer, Aimee L; Back, 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
Park, Steven I; Shenoi, Jaideep; Frayo, Shani M et al. (2011) Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma. Clin Cancer Res 17:7373-82
Gunn, Jonathan; Park, Steven I; Veiseh, Omid et al. (2011) A pretargeted nanoparticle system for tumor cell labeling. Mol Biosyst 7:742-8

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