Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers
Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125642 |
| _version_ | 1826197968156360704 |
|---|---|
| author | Green, Damian J. Frayo, Shani L. Lin, Yukang Hamlin, Donald K. Fisher, Darrell R. Frost, Sofia H.L. Kenoyer, Aimee L. Hylarides, Mark D. Gopal, Ajay K. Gooley, Theodore A. Orozco, Johnnie J. Till, Brian G. O'Steen, Shyril Orcutt, Kelly Davis Wilbur, D. Scott Wittrup, Karl Dane Press, Oliver W. |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Green, Damian J. Frayo, Shani L. Lin, Yukang Hamlin, Donald K. Fisher, Darrell R. Frost, Sofia H.L. Kenoyer, Aimee L. Hylarides, Mark D. Gopal, Ajay K. Gooley, Theodore A. Orozco, Johnnie J. Till, Brian G. O'Steen, Shyril Orcutt, Kelly Davis Wilbur, D. Scott Wittrup, Karl Dane Press, Oliver W. |
| author_sort | Green, Damian J. |
| collection | MIT |
| description | Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. |
| first_indexed | 2024-09-23T10:56:36Z |
| format | Article |
| id | mit-1721.1/125642 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:56:36Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1256422022-09-27T16:05:36Z Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers Green, Damian J. Frayo, Shani L. Lin, Yukang Hamlin, Donald K. Fisher, Darrell R. Frost, Sofia H.L. Kenoyer, Aimee L. Hylarides, Mark D. Gopal, Ajay K. Gooley, Theodore A. Orozco, Johnnie J. Till, Brian G. O'Steen, Shyril Orcutt, Kelly Davis Wilbur, D. Scott Wittrup, Karl Dane Press, Oliver W. Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Biological Engineering Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. 2020-06-03T15:00:57Z 2020-06-03T15:00:57Z 2016-09 2016-08 2019-09-13T17:24:49Z Article http://purl.org/eprint/type/JournalArticle 0008-5472 1538-7445 https://hdl.handle.net/1721.1/125642 Green, Damian J. et al., "Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers" Cancer Research 76, 22 (November 2016): 6669–6679 ©2016 AACR. en https://dx.doi.org/10.1158/0008-5472.can-16-0571 Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Green, Damian J. Frayo, Shani L. Lin, Yukang Hamlin, Donald K. Fisher, Darrell R. Frost, Sofia H.L. Kenoyer, Aimee L. Hylarides, Mark D. Gopal, Ajay K. Gooley, Theodore A. Orozco, Johnnie J. Till, Brian G. O'Steen, Shyril Orcutt, Kelly Davis Wilbur, D. Scott Wittrup, Karl Dane Press, Oliver W. Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title | Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title_full | Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title_fullStr | Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title_full_unstemmed | Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title_short | Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers |
| title_sort | comparative analysis of bispecific antibody and streptavidin targeted radioimmunotherapy for b cell cancers |
| url | https://hdl.handle.net/1721.1/125642 |
| work_keys_str_mv | AT greendamianj comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT frayoshanil comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT linyukang comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT hamlindonaldk comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT fisherdarrellr comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT frostsofiahl comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT kenoyeraimeel comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT hylaridesmarkd comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT gopalajayk comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT gooleytheodorea comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT orozcojohnniej comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT tillbriang comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT osteenshyril comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT orcuttkellydavis comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT wilburdscott comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT wittrupkarldane comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers AT pressoliverw comparativeanalysisofbispecificantibodyandstreptavidintargetedradioimmunotherapyforbcellcancers |