: Preliminary clinical trials have demonstrated that radiolabeled anti-CD2O monoclonal antibodies can achieve remissions in 65-90 percent 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 two-step 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 anti-CD2O, anti-CD22, and anti-DR antibody-SA conjugates pretargeted to lymphoma xenografts in an athymic mouse model, followed by radiobiotin administration. Second, we will investigate the pharmacokinetics, biodistributions, toxicities, and efficacies of 2 molecularly engineered recombinant tetravalent single chain antibody-SA fusion proteins ([scFv]4-SA) and compare them to standard synthetic antibody-SA chemical conjugates. Third, we will compare the relative merits of 4 genetically engineered SA mutant molecules with native SA for pretargeting protocols in combination with either biotin or a synthetic divalent bis-biotin targeting molecule. 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. Fourth, we will evaluate the pharmacokinetics, biodistributions, toxicities, and efficacies of novel molecularly designed bispecific anti-CD2O x anti-ligand Abs which possesses a molecularly engineered binding pocket capable of binding covalently to synthetic radiolabeled electrophilic ligands. These bispecific anti-CD2O x anti-ligand Abs will be compared directly to the SA-biotin pretargeting approach in lymphoma xenograft 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076287-06
Application #
6615770
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Stone, Helen B
Project Start
1998-01-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$343,272
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Green, Damian J; O'Steen, Shyril; Lin, Yukang et al. (2018) CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood 131:611-620
Greenbaum, Adam M; Green, Damian J; Holmberg, Leona A et al. (2018) Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Blood Res 53:223-226
Green, Damian J; Press, Oliver W (2017) Whither Radioimmunotherapy: To Be or Not To Be? Cancer Res 77:2191-2196
Kern, Hanna B; Srinivasan, Selvi; Convertine, Anthony J et al. (2017) Enzyme-Cleavable Polymeric Micelles for the Intracellular Delivery of Proapoptotic Peptides. Mol Pharm 14:1450-1459
O'Steen, Shyril; Green, Damian J; Gopal, Ajay K et al. (2017) Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas. Cancer Res 77:3885-3893
Orozco, Johnnie J; Kenoyer, Aimee; Balkin, Ethan R et al. (2016) Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood 127:352-9
Green, Damian J; Frayo, Shani L; Lin, Yukang et al. (2016) Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers. Cancer Res 76:6669-6679
Green, D J; Bensinger, W I; Holmberg, L A et al. (2016) Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 51:1330-1336
Cassaday, Ryan D; Stevenson, Philip A; Gooley, Theodore A et al. (2015) High-dose CD20-targeted radioimmunotherapy-based autologous transplantation improves outcomes for persistent mantle cell lymphoma. Br J Haematol 171:788-97
Frost, Sofia H L; Frayo, Shani L; Miller, Brian W et al. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One 10:e0120561

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