An Antibody‐Drug Conjugate for Multiple Myeloma Prepared by Multi‐Arm Linkers
First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide d...
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Published in | Advanced science Vol. 11; no. 20; pp. e2307852 - n/a |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Germany
John Wiley & Sons, Inc
01.05.2024
John Wiley and Sons Inc Wiley |
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Abstract | First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing “multi‐arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells.
Uncover the transformative potential of TE‐1146 to treat multiple myeloma. TE‐1146, prepared using an innovative HighDAR platform, comprises six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab. It shows enhanced target cell‐killing activity compared to daratumumab, alone or combined with lenalidomide, as it delivers lenalidomide specifically to target MM cells. Lenalidomide alone cannot easily enter cells. |
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AbstractList | First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing “multi-arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells. First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing “multi‐arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn 2+ ‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells. Uncover the transformative potential of TE‐1146 to treat multiple myeloma. TE‐1146, prepared using an innovative HighDAR platform, comprises six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab. It shows enhanced target cell‐killing activity compared to daratumumab, alone or combined with lenalidomide, as it delivers lenalidomide specifically to target MM cells. Lenalidomide alone cannot easily enter cells. First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn -binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells. Abstract First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing “multi‐arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn 2+ ‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells. Abstract First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing “multi‐arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells. First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing “multi‐arm linker” to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells. Uncover the transformative potential of TE‐1146 to treat multiple myeloma. TE‐1146, prepared using an innovative HighDAR platform, comprises six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab. It shows enhanced target cell‐killing activity compared to daratumumab, alone or combined with lenalidomide, as it delivers lenalidomide specifically to target MM cells. Lenalidomide alone cannot easily enter cells. |
Author | Lee, Hui‐Ju Chu, Hsing‐Mao Lin, Wei‐Chen Hsieh, Ming‐Yu Lim, Carmay Yu, Yueh‐Hsiang Wu, Pei‐Wen Peng, Chi‐Jiun Chang, Tse Wen Lin, Pei‐Hsuan Tian, Wei‐Ting Grauffel, Cédric |
AuthorAffiliation | 1 Immunwork, Inc. Academia Rd., Sec. 1, Nangang Taipei 115 Taiwan 2 Institute of Biomedical Sciences Academia Sinica Academia Rd. Taipei 115 Taiwan |
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Snippet | First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate... First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate... Abstract First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often... Abstract First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often... |
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SubjectTerms | Animals Antibodies Antibodies, Monoclonal - pharmacology Antigens Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use anti‐CD38 Cell Line, Tumor Chemical bonds Cytotoxicity Disease Models, Animal Humans Immunoconjugates - chemistry Immunoconjugates - pharmacology lenalidomide Lenalidomide - pharmacology Lenalidomide - therapeutic use Mice Multiple myeloma Multiple Myeloma - drug therapy Peptides Proteins scFv site‐specific conjugation Toxicity Zn2+‐binding motif |
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Title | An Antibody‐Drug Conjugate for Multiple Myeloma Prepared by Multi‐Arm Linkers |
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