Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors
Drug‐free macromolecular therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen‐crosslinking‐induced apoptosis in target cells. DFMT is a two‐component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab‐MORF1) and human serum...
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| Veröffentlicht in: | Macromolecular bioscience 2024-03, Vol.24 (3), p.e2300375-n/a |
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| creator | Gambles, M. Tommy Sborov, Douglas Shami, Paul Yang, Jiyuan Kopeček, Jindřich |
| description | Drug‐free macromolecular therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen‐crosslinking‐induced apoptosis in target cells. DFMT is a two‐component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab‐MORF1) and human serum albumin conjugated with multiple copies of complementary morpholino oligonucleotide (MORF2), (HSA‐(MORF2)x). The two components recognize each other via the Watson–Crick base pairing complementation of their respective MORFs. One HSA‐(MORF2)x molecule can hybridize with multiple Ab‐MORF1 molecules on the cell surface, thus serving as the therapeutic crosslink‐inducing mechanism of action. Herein, various anti‐neoplastic agents in combination with the anti‐CD20 Obinutuzumab (OBN)‐based DFMT system are examined. Three different classes of chemotherapies are examined: DNA alkylating agents; proliferation pathway inhibitors; and DNA replication inhibitors. Chou–Talalay combination index mathematics is utilized to determine which drugs engaged synergistically with OBN‐based DFMT. It is determined that OBN‐based DFMT synergizes with topoisomerase inhibitors and DNA nucleotide analogs but is antagonistic with proliferation pathway inhibitors. Cell mechanism experiments are performed to analyze points of synergism or antagonism by investigating Ca2+ influx, mitochondrial health, lysosomal stability, and cell cycle arrest. Finally, the synergistic drug combinatorial effects of OBN‐based DFMT with etoposide in vivo are demonstrated using a human xenograft non‐Hodgkin's lymphoma mouse model.
Synergistic chemotherapies to be used in combination with drug‐free macromolecular therapeutics (DFMT) technology are determined. DFMT is currently being explored as a new paradigm in treating B‐cell cancers. How DFMT behaves when administered in combination with clinically used anti‐neoplastic agents is of interest. Augmenting the technology with a synergistic chemotherapy could lead to improved anti‐cancer efficacy. |
| doi_str_mv | 10.1002/mabi.202300375 |
| format | Article |
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Synergistic chemotherapies to be used in combination with drug‐free macromolecular therapeutics (DFMT) technology are determined. DFMT is currently being explored as a new paradigm in treating B‐cell cancers. How DFMT behaves when administered in combination with clinically used anti‐neoplastic agents is of interest. Augmenting the technology with a synergistic chemotherapy could lead to improved anti‐cancer efficacy.</description><identifier>ISSN: 1616-5187</identifier><identifier>ISSN: 1616-5195</identifier><identifier>EISSN: 1616-5195</identifier><identifier>DOI: 10.1002/mabi.202300375</identifier><identifier>PMID: 37838941</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Alkylating agents ; Alkylation ; Animals ; Antagonism ; Antibodies, Monoclonal, Humanized - pharmacology ; Antigens, CD20 - genetics ; Antineoplastic Agents ; Apoptosis ; Calcium (mitochondrial) ; Calcium influx ; Calcium ions ; CD20 antigen ; CD20 crosslinking ; Cell cycle ; Cell surface ; chemo‐immunotherapy ; Combinations (mathematics) ; Combinatorial analysis ; Complementation ; Crosslinking ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA topoisomerase inhibitors ; drug‐free macromolecular therapeutics ; Etoposide ; Human serum albumin ; Humans ; Inhibitors ; Lymphoma ; Macromolecular Substances ; Macromolecules ; Mice ; Monoclonal antibodies ; Morpholinos ; Non-Hodgkin's lymphoma ; Nucleotide analogs ; Nucleotides ; obinutuzumab ; Oligonucleotides ; Serum albumin ; Synergism ; Topoisomerase Inhibitors ; Xenotransplantation</subject><ispartof>Macromolecular bioscience, 2024-03, Vol.24 (3), p.e2300375-n/a</ispartof><rights>2023 Wiley‐VCH GmbH</rights><rights>2023 Wiley-VCH GmbH.</rights><rights>2024 Wiley‐VCH GmbH</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4135-1dfb2c3f4aa41fb402f6715a0f8afee63708bc1ec196653f9f4bb739f11b48023</citedby><cites>FETCH-LOGICAL-c4135-1dfb2c3f4aa41fb402f6715a0f8afee63708bc1ec196653f9f4bb739f11b48023</cites><orcidid>0000-0002-4451-6944</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmabi.202300375$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmabi.202300375$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37838941$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gambles, M. Tommy</creatorcontrib><creatorcontrib>Sborov, Douglas</creatorcontrib><creatorcontrib>Shami, Paul</creatorcontrib><creatorcontrib>Yang, Jiyuan</creatorcontrib><creatorcontrib>Kopeček, Jindřich</creatorcontrib><title>Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors</title><title>Macromolecular bioscience</title><addtitle>Macromol Biosci</addtitle><description>Drug‐free macromolecular therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen‐crosslinking‐induced apoptosis in target cells. DFMT is a two‐component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab‐MORF1) and human serum albumin conjugated with multiple copies of complementary morpholino oligonucleotide (MORF2), (HSA‐(MORF2)x). The two components recognize each other via the Watson–Crick base pairing complementation of their respective MORFs. One HSA‐(MORF2)x molecule can hybridize with multiple Ab‐MORF1 molecules on the cell surface, thus serving as the therapeutic crosslink‐inducing mechanism of action. Herein, various anti‐neoplastic agents in combination with the anti‐CD20 Obinutuzumab (OBN)‐based DFMT system are examined. Three different classes of chemotherapies are examined: DNA alkylating agents; proliferation pathway inhibitors; and DNA replication inhibitors. Chou–Talalay combination index mathematics is utilized to determine which drugs engaged synergistically with OBN‐based DFMT. It is determined that OBN‐based DFMT synergizes with topoisomerase inhibitors and DNA nucleotide analogs but is antagonistic with proliferation pathway inhibitors. Cell mechanism experiments are performed to analyze points of synergism or antagonism by investigating Ca2+ influx, mitochondrial health, lysosomal stability, and cell cycle arrest. Finally, the synergistic drug combinatorial effects of OBN‐based DFMT with etoposide in vivo are demonstrated using a human xenograft non‐Hodgkin's lymphoma mouse model.
Synergistic chemotherapies to be used in combination with drug‐free macromolecular therapeutics (DFMT) technology are determined. DFMT is currently being explored as a new paradigm in treating B‐cell cancers. How DFMT behaves when administered in combination with clinically used anti‐neoplastic agents is of interest. Augmenting the technology with a synergistic chemotherapy could lead to improved anti‐cancer efficacy.</description><subject>Alkylating agents</subject><subject>Alkylation</subject><subject>Animals</subject><subject>Antagonism</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antigens, CD20 - genetics</subject><subject>Antineoplastic Agents</subject><subject>Apoptosis</subject><subject>Calcium (mitochondrial)</subject><subject>Calcium influx</subject><subject>Calcium ions</subject><subject>CD20 antigen</subject><subject>CD20 crosslinking</subject><subject>Cell cycle</subject><subject>Cell surface</subject><subject>chemo‐immunotherapy</subject><subject>Combinations (mathematics)</subject><subject>Combinatorial analysis</subject><subject>Complementation</subject><subject>Crosslinking</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA topoisomerase inhibitors</subject><subject>drug‐free macromolecular therapeutics</subject><subject>Etoposide</subject><subject>Human serum albumin</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Lymphoma</subject><subject>Macromolecular Substances</subject><subject>Macromolecules</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>Morpholinos</subject><subject>Non-Hodgkin's lymphoma</subject><subject>Nucleotide analogs</subject><subject>Nucleotides</subject><subject>obinutuzumab</subject><subject>Oligonucleotides</subject><subject>Serum albumin</subject><subject>Synergism</subject><subject>Topoisomerase Inhibitors</subject><subject>Xenotransplantation</subject><issn>1616-5187</issn><issn>1616-5195</issn><issn>1616-5195</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctOAyEUhonReN-6NJO4cdMKwwwMS623JhoX1jWB6cFiZoYKQ0xd-Qg-o08iploTN644JB9fDv-P0AHBQ4JxftIqbYc5zinGlJdraJswwgYlEeX6aq74FtoJ4QljwiuRb6ItyitaiYJsI7jTtot9fI3J9PH2fqYCTLNzHx_T5dIDZLeq9q51DdSxUT6bzMCrOcTe1iG7X3TgH-0rhOzF9rNs4ubOBtcmJEA27mZW2975sIc2jGoC7H-fu-jh8mIyuh7c3F2NR6c3g7ogtByQqdF5TU2hVEGMLnBuGCelwqZSBoBRjitdE6iJYKykRphCa06FIUQXVQphFx0vvXPvniOEXrY21NA0qgMXg8wrztPHMWMJPfqDPrnou7SdzEXJmMCiEIkaLqmUQQgejJx72yq_kATLrwLkVwFyVUB6cPitjbqF6Qr_STwBYgm82AYW_-jk7enZ-Ff-CcH-lXY</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Gambles, M. Tommy</creator><creator>Sborov, Douglas</creator><creator>Shami, Paul</creator><creator>Yang, Jiyuan</creator><creator>Kopeček, Jindřich</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4451-6944</orcidid></search><sort><creationdate>202403</creationdate><title>Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors</title><author>Gambles, M. Tommy ; Sborov, Douglas ; Shami, Paul ; Yang, Jiyuan ; Kopeček, Jindřich</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4135-1dfb2c3f4aa41fb402f6715a0f8afee63708bc1ec196653f9f4bb739f11b48023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alkylating agents</topic><topic>Alkylation</topic><topic>Animals</topic><topic>Antagonism</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Antigens, CD20 - genetics</topic><topic>Antineoplastic Agents</topic><topic>Apoptosis</topic><topic>Calcium (mitochondrial)</topic><topic>Calcium influx</topic><topic>Calcium ions</topic><topic>CD20 antigen</topic><topic>CD20 crosslinking</topic><topic>Cell cycle</topic><topic>Cell surface</topic><topic>chemo‐immunotherapy</topic><topic>Combinations (mathematics)</topic><topic>Combinatorial analysis</topic><topic>Complementation</topic><topic>Crosslinking</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA biosynthesis</topic><topic>DNA topoisomerase inhibitors</topic><topic>drug‐free macromolecular therapeutics</topic><topic>Etoposide</topic><topic>Human serum albumin</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Lymphoma</topic><topic>Macromolecular Substances</topic><topic>Macromolecules</topic><topic>Mice</topic><topic>Monoclonal antibodies</topic><topic>Morpholinos</topic><topic>Non-Hodgkin's lymphoma</topic><topic>Nucleotide analogs</topic><topic>Nucleotides</topic><topic>obinutuzumab</topic><topic>Oligonucleotides</topic><topic>Serum albumin</topic><topic>Synergism</topic><topic>Topoisomerase Inhibitors</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gambles, M. Tommy</creatorcontrib><creatorcontrib>Sborov, Douglas</creatorcontrib><creatorcontrib>Shami, Paul</creatorcontrib><creatorcontrib>Yang, Jiyuan</creatorcontrib><creatorcontrib>Kopeček, Jindřich</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Macromolecular bioscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gambles, M. Tommy</au><au>Sborov, Douglas</au><au>Shami, Paul</au><au>Yang, Jiyuan</au><au>Kopeček, Jindřich</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors</atitle><jtitle>Macromolecular bioscience</jtitle><addtitle>Macromol Biosci</addtitle><date>2024-03</date><risdate>2024</risdate><volume>24</volume><issue>3</issue><spage>e2300375</spage><epage>n/a</epage><pages>e2300375-n/a</pages><issn>1616-5187</issn><issn>1616-5195</issn><eissn>1616-5195</eissn><abstract>Drug‐free macromolecular therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen‐crosslinking‐induced apoptosis in target cells. DFMT is a two‐component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab‐MORF1) and human serum albumin conjugated with multiple copies of complementary morpholino oligonucleotide (MORF2), (HSA‐(MORF2)x). The two components recognize each other via the Watson–Crick base pairing complementation of their respective MORFs. One HSA‐(MORF2)x molecule can hybridize with multiple Ab‐MORF1 molecules on the cell surface, thus serving as the therapeutic crosslink‐inducing mechanism of action. Herein, various anti‐neoplastic agents in combination with the anti‐CD20 Obinutuzumab (OBN)‐based DFMT system are examined. Three different classes of chemotherapies are examined: DNA alkylating agents; proliferation pathway inhibitors; and DNA replication inhibitors. Chou–Talalay combination index mathematics is utilized to determine which drugs engaged synergistically with OBN‐based DFMT. It is determined that OBN‐based DFMT synergizes with topoisomerase inhibitors and DNA nucleotide analogs but is antagonistic with proliferation pathway inhibitors. Cell mechanism experiments are performed to analyze points of synergism or antagonism by investigating Ca2+ influx, mitochondrial health, lysosomal stability, and cell cycle arrest. Finally, the synergistic drug combinatorial effects of OBN‐based DFMT with etoposide in vivo are demonstrated using a human xenograft non‐Hodgkin's lymphoma mouse model.
Synergistic chemotherapies to be used in combination with drug‐free macromolecular therapeutics (DFMT) technology are determined. DFMT is currently being explored as a new paradigm in treating B‐cell cancers. How DFMT behaves when administered in combination with clinically used anti‐neoplastic agents is of interest. Augmenting the technology with a synergistic chemotherapy could lead to improved anti‐cancer efficacy.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37838941</pmid><doi>10.1002/mabi.202300375</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-4451-6944</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alkylating agents Alkylation Animals Antagonism Antibodies, Monoclonal, Humanized - pharmacology Antigens, CD20 - genetics Antineoplastic Agents Apoptosis Calcium (mitochondrial) Calcium influx Calcium ions CD20 antigen CD20 crosslinking Cell cycle Cell surface chemo‐immunotherapy Combinations (mathematics) Combinatorial analysis Complementation Crosslinking Deoxyribonucleic acid DNA DNA biosynthesis DNA topoisomerase inhibitors drug‐free macromolecular therapeutics Etoposide Human serum albumin Humans Inhibitors Lymphoma Macromolecular Substances Macromolecules Mice Monoclonal antibodies Morpholinos Non-Hodgkin's lymphoma Nucleotide analogs Nucleotides obinutuzumab Oligonucleotides Serum albumin Synergism Topoisomerase Inhibitors Xenotransplantation |
| title | Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors |
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