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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

Open Access 01-12-2020 | Rapid communication

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

Authors: 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

Published in: Journal of Hematology & Oncology | Issue 1/2020

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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.
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Metadata
Title
CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110
Authors
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
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00865-7

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Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

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