Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) are promising state-of-the-art biopharmaceutical drugs for selective drug-delivery applications and the treatment of diseases such as cancer. The idea behind the ADC technology is remarkable as it combines the highly selective targeting capacity of monoclonal antibodi...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-12-01
|
| Series: | Separations |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2297-8739/6/1/1 |
| _version_ | 1828275170342600704 |
|---|---|
| author | Filip S. Ekholm Suvi-Katriina Ruokonen Marina Redón Virve Pitkänen Anja Vilkman Juhani Saarinen Jari Helin Tero Satomaa Susanne K. Wiedmer |
| author_facet | Filip S. Ekholm Suvi-Katriina Ruokonen Marina Redón Virve Pitkänen Anja Vilkman Juhani Saarinen Jari Helin Tero Satomaa Susanne K. Wiedmer |
| author_sort | Filip S. Ekholm |
| collection | DOAJ |
| description | Antibody-drug conjugates (ADCs) are promising state-of-the-art biopharmaceutical drugs for selective drug-delivery applications and the treatment of diseases such as cancer. The idea behind the ADC technology is remarkable as it combines the highly selective targeting capacity of monoclonal antibodies with the cancer-killing ability of potent cytotoxic agents. The continuous development of improved ADCs requires systematic studies on the nature and effects of warhead modification. Recently, we focused on the hydrophilic modification of monomethyl auristatin E (MMAE), the most widely used cytotoxic agent in current clinical trial ADCs. Herein, we report on the use of micellar electrokinetic chromatography (MEKC) for studying the hydrophobic character of modified MMAE derivatives. Our data reveal a connection between the hydrophobicity of the modified warheads as free molecules and their cytotoxic activity. In addition, MMAE-trastuzumab ADCs were constructed and evaluated in preliminary cytotoxic assays. |
| first_indexed | 2024-04-13T06:46:02Z |
| format | Article |
| id | doaj.art-ce3bcce3ae8246aabae69be02a0c9af4 |
| institution | Directory Open Access Journal |
| issn | 2297-8739 |
| language | English |
| last_indexed | 2024-04-13T06:46:02Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Separations |
| spelling | doaj.art-ce3bcce3ae8246aabae69be02a0c9af42022-12-22T02:57:35ZengMDPI AGSeparations2297-87392018-12-0161110.3390/separations6010001separations6010001Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug ConjugatesFilip S. Ekholm0Suvi-Katriina Ruokonen1Marina Redón2Virve Pitkänen3Anja Vilkman4Juhani Saarinen5Jari Helin6Tero Satomaa7Susanne K. Wiedmer8Department of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, FI 00014 Helsinki, FinlandDepartment of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, FI 00014 Helsinki, FinlandDepartment of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, FI 00014 Helsinki, FinlandGlykos Finland Ltd., Viikinkaari 6, 00790 Helsinki, FinlandGlykos Finland Ltd., Viikinkaari 6, 00790 Helsinki, FinlandGlykos Finland Ltd., Viikinkaari 6, 00790 Helsinki, FinlandGlykos Finland Ltd., Viikinkaari 6, 00790 Helsinki, FinlandGlykos Finland Ltd., Viikinkaari 6, 00790 Helsinki, FinlandDepartment of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, FI 00014 Helsinki, FinlandAntibody-drug conjugates (ADCs) are promising state-of-the-art biopharmaceutical drugs for selective drug-delivery applications and the treatment of diseases such as cancer. The idea behind the ADC technology is remarkable as it combines the highly selective targeting capacity of monoclonal antibodies with the cancer-killing ability of potent cytotoxic agents. The continuous development of improved ADCs requires systematic studies on the nature and effects of warhead modification. Recently, we focused on the hydrophilic modification of monomethyl auristatin E (MMAE), the most widely used cytotoxic agent in current clinical trial ADCs. Herein, we report on the use of micellar electrokinetic chromatography (MEKC) for studying the hydrophobic character of modified MMAE derivatives. Our data reveal a connection between the hydrophobicity of the modified warheads as free molecules and their cytotoxic activity. In addition, MMAE-trastuzumab ADCs were constructed and evaluated in preliminary cytotoxic assays.http://www.mdpi.com/2297-8739/6/1/1antibody-drug conjugatebiopharmaceuticalcytotoxicityhydrophobicitymicellar electrokinetic chromatography |
| spellingShingle | Filip S. Ekholm Suvi-Katriina Ruokonen Marina Redón Virve Pitkänen Anja Vilkman Juhani Saarinen Jari Helin Tero Satomaa Susanne K. Wiedmer Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates Separations antibody-drug conjugate biopharmaceutical cytotoxicity hydrophobicity micellar electrokinetic chromatography |
| title | Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates |
| title_full | Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates |
| title_fullStr | Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates |
| title_full_unstemmed | Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates |
| title_short | Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates |
| title_sort | hydrophilic monomethyl auristatin e derivatives as novel candidates for the design of antibody drug conjugates |
| topic | antibody-drug conjugate biopharmaceutical cytotoxicity hydrophobicity micellar electrokinetic chromatography |
| url | http://www.mdpi.com/2297-8739/6/1/1 |
| work_keys_str_mv | AT filipsekholm hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT suvikatriinaruokonen hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT marinaredon hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT virvepitkanen hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT anjavilkman hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT juhanisaarinen hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT jarihelin hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT terosatomaa hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates AT susannekwiedmer hydrophilicmonomethylauristatinederivativesasnovelcandidatesforthedesignofantibodydrugconjugates |