CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110
Abstract Background In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-04-01
|
| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13045-020-00865-7 |
| _version_ | 1819169505482375168 |
|---|---|
| author | Juan Manuel Domínguez Gema Pérez-Chacón María José Guillén María José Muñoz-Alonso Beatriz Somovilla-Crespo Danay Cibrián Bárbara Acosta-Iborra Magdalena Adrados Cecilia Muñoz-Calleja Carmen Cuevas Francisco Sánchez-Madrid Pablo Avilés Juan M. Zapata |
| author_facet | Juan Manuel Domínguez Gema Pérez-Chacón María José Guillén María José Muñoz-Alonso Beatriz Somovilla-Crespo Danay Cibrián Bárbara Acosta-Iborra Magdalena Adrados Cecilia Muñoz-Calleja Carmen Cuevas Francisco Sánchez-Madrid Pablo Avilés Juan M. Zapata |
| author_sort | Juan Manuel Domínguez |
| collection | DOAJ |
| description | Abstract Background In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. Conclusion Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent. |
| first_indexed | 2024-12-22T19:20:34Z |
| format | Article |
| id | doaj.art-38476467c1d24e7b8130be99558bbb30 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-22T19:20:34Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-38476467c1d24e7b8130be99558bbb302022-12-21T18:15:23ZengBMCJournal of Hematology & Oncology1756-87222020-04-0113111510.1186/s13045-020-00865-7CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110Juan Manuel Domínguez0Gema Pérez-Chacón1María José Guillén2María José Muñoz-Alonso3Beatriz Somovilla-Crespo4Danay Cibrián5Bárbara Acosta-Iborra6Magdalena Adrados7Cecilia Muñoz-Calleja8Carmen Cuevas9Francisco Sánchez-Madrid10Pablo Avilés11Juan M. Zapata12Research Department, PharmaMar S.A.Instituto de Investigaciones Biomedicas “Alberto Sols”, CSIC-UAMResearch Department, PharmaMar S.A.Research Department, PharmaMar S.A.Department of Immunology, Instituto de Investigacion Sanitaria Hospital de la Princesa, IIS-IPDepartment of Immunology, Instituto de Investigacion Sanitaria Hospital de la Princesa, IIS-IPInstituto de Investigaciones Biomedicas “Alberto Sols”, CSIC-UAMDepartment of Pathology, Instituto de Investigacion Sanitaria Hospital de la Princesa, IIS-IPDepartment of Immunology, Instituto de Investigacion Sanitaria Hospital de la Princesa, IIS-IPResearch Department, PharmaMar S.A.Department of Immunology, Instituto de Investigacion Sanitaria Hospital de la Princesa, IIS-IPResearch Department, PharmaMar S.A.Instituto de Investigaciones Biomedicas “Alberto Sols”, CSIC-UAMAbstract Background In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. Conclusion Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.http://link.springer.com/article/10.1186/s13045-020-00865-7CD13ADCAntibody-drug conjugateMI130110FibrosarcomaEndocytosis |
| spellingShingle | Juan Manuel Domínguez Gema Pérez-Chacón María José Guillén María José Muñoz-Alonso Beatriz Somovilla-Crespo Danay Cibrián Bárbara Acosta-Iborra Magdalena Adrados Cecilia Muñoz-Calleja Carmen Cuevas Francisco Sánchez-Madrid Pablo Avilés Juan M. Zapata CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 Journal of Hematology & Oncology CD13 ADC Antibody-drug conjugate MI130110 Fibrosarcoma Endocytosis |
| title | CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 |
| title_full | CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 |
| title_fullStr | CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 |
| title_full_unstemmed | CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 |
| title_short | CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110 |
| title_sort | cd13 as a new tumor target for antibody drug conjugates validation with the conjugate mi130110 |
| topic | CD13 ADC Antibody-drug conjugate MI130110 Fibrosarcoma Endocytosis |
| url | http://link.springer.com/article/10.1186/s13045-020-00865-7 |
| work_keys_str_mv | AT juanmanueldominguez cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT gemaperezchacon cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT mariajoseguillen cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT mariajosemunozalonso cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT beatrizsomovillacrespo cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT danaycibrian cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT barbaraacostaiborra cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT magdalenaadrados cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT ceciliamunozcalleja cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT carmencuevas cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT franciscosanchezmadrid cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT pabloaviles cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 AT juanmzapata cd13asanewtumortargetforantibodydrugconjugatesvalidationwiththeconjugatemi130110 |