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The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The activity of monoclonal antibodies in this instance is quite low. An improved strategy is to attach an anti-cancer drug to the antibody in the form of an antibody-drug conjugate, which can facilitate the selective delivery of the anti-cancer drug to specific types of cancer cells. This selectivity is highly desirable because, for many anti-cancer drugs, the concentration needed for the effective treatment of cancer is close to the threshold concentration for toxicity.
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Antibody drug conjugates (ADCs), serving as carriers of cell-killing toxins directly to the target cell, possess several possible cell killing actions; the cell-killing action of the conjugate payload to the mab, along with the mab’s inherent cell killing by cell cytotoxicity and also mab binding to cells, fostering immune reactions against the cell–mab complex. The payloads can be toxic chemicals (e.g., calecheamycin, emtansine), cell toxins (e.g., ricin), bacterial toxins (e.g., diphtheria), or radioactive nuclides (e.g., Indium-111, Yrttium-90), producing localized radiation. Conjugation also involves the use of a linker molecule that binds the payload to the mab. The properties and traits of the ADC and its components are listed further in Table 5.2.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
Future directions for the more effective utilization of monoclonal antibodies as drug targeting agents must focus on a more rational design of the antibody-drug conjugate. Earlier studies have focused on the development of bispecific antibodies combining the VH and VL of two different antibodies into one molecule to ensure cellular targeting constitutes an effective disease treatment (van Spriel et al. 2000). In particular, these studies have shown that the chemistry of the linker groups in relation to release mechanisms at the site of action must be carefully evaluated. In addition, chemical entities that could be incorporated into the conjugate structure that may influence its biodistribution should also be investigated. Also, more emphasis should be placed on determining the precise mechanism of action to avoid misinterpretation of in vivo data. In instances where a therapeutic effect has been observed, little attempt has been made to determine whether site specificity has been achieved by the proposed mechanism. Finally, with the increasing availability of human monoclonal antibodies, it is clear that drug-antibody conjugates have even greater potential for clinical therapy, although the cost of manufacturing and purifying monoclonal antibodies still limits their clinical utility.
Antibody therapeutics for epithelial ovarian cancer
Published in Expert Opinion on Biological Therapy, 2022
Mason Ruiz, Ningyan Zhang, Anil K Sood, Zhiqiang An
Antibody-based drug modalities such as monoclonal antibodies, antibody drug conjugates, bi-specifics, bi-specific T-cell engagers have made significant advancements in the treatment of diseases compared to other therapeutic modalities in the last 20 years. The vast number of antibody therapeutics in pre-clinical and clinical trials will significantly impact patient care for the better. We believe that antibody therapeutics, especially antibody drug-conjugates and bispecific T-cell engagers, will become the major drug modality in ovarian cancer. While antibody drug conjugates have demonstrated promising preclinical and clinical success, toxicity remains a concern and should be carefully considered. Properties such as drug-antibody ratio and drug linker can greatly affect PK properties and need to be evaluated when trying to maximize clinical activity and minimize side effects.
Emerging HER2-directed therapeutic agents for gastric cancer in early phase clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
The antibody-drug conjugate trastuzumab deruxtecan displays promising activity in pretreated HER2 positive inoperable gastric cancer phase 2 trials with ORR as the primary endpoint. This caused excitement in the gastrointestinal cancer community because it is rare to see complete responses in heavily pretreated patients. Randomized phase 3 clinical trials of second-line trastuzumab deruxtecan with OS as the primary endpoint are underway. Numerous HER2-directed antibody drug conjugates are in early phase clinical trials for pretreated HER2 positive gastric cancer and RC-48 has entered phase 3 clinical trials although response rates are much lower than for trastuzumab deruxtecan. Antibody-drug conjugates can cause interstitial lung disease, pneumonitis, and ocular toxicity and patients should be appropriately counselled, monitored, and managed. The payload bound to the antibody may affect safety and clinical response.
Antibody-drug conjugates for the treatment of ovarian cancer
Published in Expert Opinion on Biological Therapy, 2021
Corinne A. Calo, David M. O’Malley
Antibody-drug conjugates represent a unique form of targeted therapy that utilize antigen-specific interactions to deliver potent cytotoxic therapy directly to tumor cells with a primary goal of limiting systemic toxicity. They have demonstrated favorable clinical response rates in patients with platinum-resistant, recurrent ovarian cancer ranging from 5% to 45%. When ADC use is tailored to patients with high expression of the target antigen, these response rates are improved (overall response rates of 26–46%). The most promising data, however, seem lie in combination therapy with response rates ranging from 52% to 80%. These response rates in conjunction with a tolerable safety profile make ADCs an attractive treatment option in this patient population with limited options. While there is currently only one ADC under phase 3 investigation in ovarian cancer, the field is rapidly expanding and evolving with many new trials investigating the use of ADCs in ovarian cancer on the horizon.