scholarly journals Antibody-Drug Conjugates: Patient and Treatment Selection

2020 ◽  
pp. 105-114
Author(s):  
Shalini Makawita ◽  
Funda Meric-Bernstam
Keyword(s):  
Patient Selection ◽  
Therapeutic Efficacy ◽  
Antigen Expression ◽  
Therapeutic Modality ◽  
Intratumor Heterogeneity ◽  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Impact ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are a promising drug platform designed to enhance the therapeutic index and minimize the toxicity of anticancer agents. ADCs have experienced substantial progress and technological growth over the past decades; however, several challenges to patient selection and treatment remain. Methods to optimally capture all patients who may benefit from a particular ADC are still largely unknown. Although target antigen expression remains a biomarker for patient selection, the impact of intratumor heterogeneity on antigen expression, as well as the dynamic changes in expression with treatment and disease progression, are important considerations in patient selection. Better understanding of these factors, as well as minimum levels of target antigen expression required to achieve therapeutic efficacy, will enable further optimization of selection strategies. Other important considerations include understanding mechanisms of primary and acquired resistance to ADCs. Ongoing efforts in the design of its constituent parts to possess the intrinsic ability to overcome these mechanisms, including use of the “bystander effect” to enhance efficacy in heterogeneous or low target antigen-expressing tumors, as well as modulation of the chemical and immunophenotypic properties of antibodies and linker molecules to improve payload sensitivity and therapeutic efficacy, are under way. These strategies may also lead to improved safety profiles. Similarly, combination strategies using ADCs with other cytotoxic or immunomodulatory agents are also under development. Great strides have been made in ADC technology. With further refinements, this therapeutic modality has the potential to make an important clinical impact on a wider range of tumor types.

scholarly journals Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2898
Author(s):  
Chiara Corti ◽  
Federica Giugliano ◽  
Eleonora Nicolò ◽  
Liliana Ascione ◽  
Giuseppe Curigliano
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Metastatic Breast ◽  
Therapeutic Index ◽  
Cytotoxic Agents ◽  
Target Antigen ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

scholarly journals Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen

2006 ◽  
Vol 66 (6) ◽  
pp. 3214-3221 ◽  
Author(s):  
Yelena V. Kovtun ◽  
Charlene A. Audette ◽  
Yumei Ye ◽  
Hongsheng Xie ◽  
Mary F. Ruberti ◽  
...  
Keyword(s):  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Heterogeneous Expression ◽  
Antibody Drug

scholarly journals Investigating the Impact of Sample Preparation on Mass Spectrometry-Based Drug-To-Antibody Ratio Determination for Cysteine- and Lysine-Linked Antibody–Drug Conjugates

Antibodies ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 46
Author(s):  
Malin Källsten ◽  
Rafael Hartmann ◽  
Lucia Kovac ◽  
Fredrik Lehmann ◽  
Sara Bergström Lind ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Sample Preparation ◽  
Reversed Phase ◽  
Sample Treatment ◽  
Antibody Molecule ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Impact ◽  
Antibody Ratio ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are heterogeneous biotherapeutics and differ vastly in their physicochemical properties depending on their design. The number of small drug molecules covalently attached to each antibody molecule is commonly referred to as the drug-to-antibody ratio (DAR). Established analytical protocols for mass spectrometry (MS)-investigation of antibodies and ADCs often require sample treatment such as desalting or interchain disulfide bond reduction prior to analysis. Herein, the impact of the desalting and reduction steps—as well as the sample concentration and elapsed time between synthesis and analysis of DAR-values (as acquired by reversed phase liquid chromatography MS (RPLC–MS))—was investigated. It was found that the apparent DAR-values could fluctuate by up to 0.6 DAR units due to changes in the sample preparation workflow. For methods involving disulfide reduction by means of dithiothreitol (DTT), an acidic quench is recommended in order to increase DAR reliability. Furthermore, the addition of a desalting step was shown to benefit the ionization efficiencies in RPLC–MS. Finally, in the case of delayed analyses, samples can be stored at four degrees Celsius for up to one week but are better stored at −20 °C for longer periods of time. In conclusion, the results demonstrate that commonly used sample preparation procedures and storage conditions themselves may impact MS-derived DAR-values, which should be taken into account when evaluating analytical procedures.

scholarly journals Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2861
Author(s):  
David Dahlgren ◽  
Hans Lennernäs
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Delivery ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Cytotoxic Drug ◽  
Target Antigen ◽  
Target Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

scholarly journals Advances and Limitations of Antibody Drug Conjugates for Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 872
Author(s):  
Candice Maria Mckertish ◽  
Veysel Kayser
Keyword(s):  
Therapeutic Index ◽  
Narrow Therapeutic Index ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Stability ◽  
Drug Antibody Ratio ◽  
Chemotherapy Agents ◽  
The Impact ◽  
Antibody Ratio ◽  
Antibody Drug

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

scholarly journals Antibody Drug Conjugates in Glioblastoma – Is There a Future for Them?

2021 ◽  
Vol 11 ◽  
Author(s):  
Sagun Parakh ◽  
Joseph Nicolazzo ◽  
Andrew M Scott ◽  
Hui Kong Gan
Keyword(s):  
Therapeutic Potential ◽  
Antigen Expression ◽  
Tumour Volume ◽  
Factors Affecting ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Limited Success ◽  
Immunosuppressive Tumor Microenvironment ◽  
Reduced Toxicity ◽  
Antibody Drug

Glioblastoma (GBM) is an aggressive and fatal malignancy that despite decades of trials has limited therapeutic options. Antibody drug conjugates (ADCs) are composed of a monoclonal antibody which specifically recognizes a cellular surface antigen linked to a cytotoxic payload. ADCs have demonstrated superior efficacy and/or reduced toxicity in a range of haematological and solid tumors resulting in nine ADCs receiving regulatory approval. ADCs have also been explored in patients with brain tumours but with limited success to date. While earlier generations ADCs in glioma patients have had limited success and high toxicity, newer and improved ADCs characterised by low immunogenicity and more effective payloads have shown promise in a range of tumour types. These newer ADCs have also been tested in glioma patients, however, with mixed results. Factors affecting the effectiveness of ADCs to target the CNS include the blood brain barrier which acts as a physical and biochemical barrier, the pro-cancerogenic and immunosuppressive tumor microenvironment and tumour characteristics like tumour volume and antigen expression. In this paper we review the data regarding the ongoing the development of ADCs in glioma patients as well as potential strategies to overcome these barriers to maximise their therapeutic potential.

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