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EP38623
Abstract: Different ADCs may have large differences in these three core components, which may affect their pharmacological properties, efficacy and safety. To learn more about ADCs, start by understanding their structure. Based on a document published by Nat Rev Clin Oncol in June 2021, let's start with 12 ADCs that have already been launched.
A Brief History of ADC Development
The concept of ADC can be traced back to the early 20th century, when scientist Paul Ehrlich conceived of a "magic bullet" that can release cytotoxic drugs. However, the entry of ADCs into oncology clinical trials began in the 1980s. No survival benefit was shown, but significant toxicity was observed, and this continued for 20 years until the CD33-targeting drug gemtuzumab ozogamicin was approved (In 2000, the first indication was relapsed or refractory acute myeloid leukemia), and it was also the first ADC approved by the US FDA. However, it was delisted in 2010 due to adverse reactions.
In 2011, the CD30-targeting drug brentuximab vedotin was approved for the treatment of classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Soon after, in 2013, the HER2-targeting drug adotrastuzumab emtansine (T-DM1) was launched. Since then, the pace of ADC research and development has gradually accelerated. The table below summarizes the 12 ADCs that have been launched.
The 12 ADCs are: Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox, Polatuzumab vedotin, Enfortumab vedotin, Trastuzumab deruxtecan, Sacituzumab govitecan, Belantamab mafodotin, Loncastuximab tesirine and Tisotumab vedotin.
Antibody And Target Selection
Immunoglobulin G (IgG) is the main antibody backbone in ADCs. Human IgG comprises four subclasses: IgGl, IgG2, IgG3 and IgG4, which differ in their constant domains and hinge regions. These differences affect the solubility and half-life of monoclonal antibodies (mAbs), as well as their affinity for different Fcγ receptors (FcγRs) expressed on immune effector cells.
Currently, most ADCs use IgG1 as the antibody backbone, and a few use IgG2 or IgG4 (eg, gemtuzumab ozogamicin and inotuzumab ozogamicin, both of which use IgG4). Compared with IgG2 and IgG4, IgG1 has similar plasma half-life, but higher complement fixation and FcγR binding. IgG3 is probably the most immunogenic subclass, but it is generally avoided in ADC design due to its short circulating half-life.Summary: Antibody-drug Conjugates (ADCs) are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. It is a hot topic of drug development in the oncology field. All ADCs contain three core components: an antibody that binds to tumor-associated antigens, a cytotoxic payload, and a linker. Each core component has complex interactions with the tumor and the tReferences: 1. Jie Wang, et al., Delivery of siRNA Therapeutics Barriers and Carriers, The AAPS Journal, 2010
2. Akin Akinc, et al., The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs, Nature Nanotechnology, 2019
3. Aaron D. Springer, et al., GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics, Nucleic Acid Therapeutics, 2018
4. Jayesh A. Kulkarni, et al., The current landscape of nucleic acid therapeutics, Nature Nanotechnology, 2021
5. Tracy S. Zimmermann, et al., Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate, Molecular Therapy, 2017
A Brief History of ADC Development
The concept of ADC can be traced back to the early 20th century, when scientist Paul Ehrlich conceived of a "magic bullet" that can release cytotoxic drugs. However, the entry of ADCs into oncology clinical trials began in the 1980s. No survival benefit was shown, but significant toxicity was observed, and this continued for 20 years until the CD33-targeting drug gemtuzumab ozogamicin was approved (In 2000, the first indication was relapsed or refractory acute myeloid leukemia), and it was also the first ADC approved by the US FDA. However, it was delisted in 2010 due to adverse reactions.
In 2011, the CD30-targeting drug brentuximab vedotin was approved for the treatment of classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Soon after, in 2013, the HER2-targeting drug adotrastuzumab emtansine (T-DM1) was launched. Since then, the pace of ADC research and development has gradually accelerated. The table below summarizes the 12 ADCs that have been launched.
The 12 ADCs are: Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox, Polatuzumab vedotin, Enfortumab vedotin, Trastuzumab deruxtecan, Sacituzumab govitecan, Belantamab mafodotin, Loncastuximab tesirine and Tisotumab vedotin.
Antibody And Target Selection
Immunoglobulin G (IgG) is the main antibody backbone in ADCs. Human IgG comprises four subclasses: IgGl, IgG2, IgG3 and IgG4, which differ in their constant domains and hinge regions. These differences affect the solubility and half-life of monoclonal antibodies (mAbs), as well as their affinity for different Fcγ receptors (FcγRs) expressed on immune effector cells.
Currently, most ADCs use IgG1 as the antibody backbone, and a few use IgG2 or IgG4 (eg, gemtuzumab ozogamicin and inotuzumab ozogamicin, both of which use IgG4). Compared with IgG2 and IgG4, IgG1 has similar plasma half-life, but higher complement fixation and FcγR binding. IgG3 is probably the most immunogenic subclass, but it is generally avoided in ADC design due to its short circulating half-life.Summary: Antibody-drug Conjugates (ADCs) are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. It is a hot topic of drug development in the oncology field. All ADCs contain three core components: an antibody that binds to tumor-associated antigens, a cytotoxic payload, and a linker. Each core component has complex interactions with the tumor and the tReferences: 1. Jie Wang, et al., Delivery of siRNA Therapeutics Barriers and Carriers, The AAPS Journal, 2010
2. Akin Akinc, et al., The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs, Nature Nanotechnology, 2019
3. Aaron D. Springer, et al., GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics, Nucleic Acid Therapeutics, 2018
4. Jayesh A. Kulkarni, et al., The current landscape of nucleic acid therapeutics, Nature Nanotechnology, 2021
5. Tracy S. Zimmermann, et al., Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate, Molecular Therapy, 2017
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