CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110
Juan Manuel Domínguez1, Gema Pérez-Chacón2,3, María José Guillén1
1Research Department, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
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.
Insights
A novel antibody-drug conjugate (ADC), MI130110, targeting CD13-expressing tumors demonstrated significant antitumor activity. This targeted therapy, combining an anti-CD13 antibody with a cytotoxic payload, shows promise for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Identifying novel targets for antibody-drug conjugates (ADCs) is crucial for therapeutic development.
- CD13 is a promising ADC target due to its differential expression in tumors and internalization upon antibody binding.
- PM050489 is a potent cytotoxic agent targeting tubulin, currently in clinical trials for solid tumors.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) targeting the CD13 antigen.
- To assess the in vitro and in vivo efficacy and specificity of the anti-CD13 ADC, MI130110.
Main Methods:
- An anti-CD13 monoclonal antibody (mAb), TEA1/8, was conjugated to the cytotoxic compound PM050489 to create the ADC MI130110.
- In vitro studies assessed MI130110's binding, internalization, cytotoxicity, and effects on cell cycle and apoptosis in CD13-expressing and CD13-null cell lines.
- In vivo efficacy was evaluated in murine xenograft models using CD13-positive fibrosarcoma and CD13-negative myeloma cells.
Main Results:
- MI130110 retained the binding and internalization properties of the anti-CD13 antibody.
- In vitro, MI130110 exhibited potent and selective cytotoxicity against CD13-expressing tumor cells, inducing cell cycle arrest and cell death.
- In vivo, MI130110 demonstrated significant antitumor activity in a CD13-positive fibrosarcoma model, leading to complete tumor remission in many animals, while showing no activity in a CD13-negative myeloma model.
Conclusions:
- MI130110 effectively combines the cytotoxic payload PM050489 with the targeted delivery of the anti-CD13 antibody TEA1/8.
- The study confirms CD13 as a suitable target for ADCs and MI130110 as a promising therapeutic agent for CD13-positive cancers.
