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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.
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.
Engineered Nanoparticles for Drug Delivery in Cancer Therapy *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Tianmeng Sun, Yu Shrike Zhang, Pang Bo, Dong Choon Hyun, Miaoxin Yang, Younan Xia
This class of drug delivery system is based on the direct conjugation of drug molecules to proteins for targeted drug delivery. When an antibody is used, the system is also known as antibody–drug conjugate (ADC) [270]. The linker between the protein and the drug is often biodegradable, capable of setting both parts free upon appropriate stimulation. The simplicity of this system lends both pros and cons to itself. The biggest advantage arises from the small size (ca. 10 nm) of such conjugates, which gives them relatively long circulation half-lives [271], and makes their extravasation into tumor sites much easier compared to nanoparticles with larger sizes, even for conjugates lacking ligands for active targeting. As for the shortcomings, not all drugs can be readily conjugated to proteins, as the structural sensitivity of certain drugs may exclude them from any chemical modifications. In addition, the stability of drug–protein linkers can be a matter of concern as the linkers tend to be rapidly degraded by proteases and redox-altering agents during plasma circulation [271, 272]. It is generally believed that protease-cleavable linkers are more stable than disulfides or other linkers, although the stability of all of them can be tailored [271, 273]. Furthermore, the ability to induce multiple functionality to the conjugates is somewhat limited. Despite these disadvantages, technological advancement in the development of new protein carriers (e.g., monoclonal antibodies), drugs, and especially linkers has greatly improved the capability of ADCs as potent therapeutics. Newer generations of products have been shown with greatly improved systemic stability, where the linkers can be held in place until the conjugates arrive at the targeted site, allowing for more precise and controllable delivery of cytotoxic agents [270c, 274].
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 next steps will be to evaluate the upcoming phase 3 data on trastuzumab deruxtecan and RC-48 which are likely to emerge within the next 1–2 years. The sheer number of early phase clinical trials evaluating HER2-directed antibody-drug conjugates are testament to the promise these drugs hold. Over the next few years, it will become clear which of the antibody drug conjugates described in this section display efficacy in early phase clinical trials and can progress to larger phase 2 and phase 3 clinical trials in HER2 positive gastric cancer. Some early phase clinical trials were terminated due to safety issues and an important next step will be learning how to manage the clinical side-effects of antibody-drug conjugates. Interstitial lung disease, pneumonitis, and ocular side-effects appear to be particularly prominent: interstitial lung disease and pneumonitis occurred in 10% of patients in the Destiny-Gastric01 trial [9] and 7.6% of patients in the Destiny-Gastric02 trial [46]. Patients should be appropriately counselled, monitored, and managed when treated with antibody drug conjugates in order to ensure quality of life is not impaired.
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.