Impact of Drug Conjugation and Loading on Target Antigen Binding and Cytotoxicity in Cysteine Antibody–Drug Conjugates

2021 ◽  
Author(s):  
Durgesh V. Nadkarni ◽  
Jamie Lee ◽  
Qingping Jiang ◽  
Vimalkumar Patel ◽  
Verl Sriskanda ◽  
...  
Keyword(s):  
Target Antigen ◽  
Antigen Binding ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Antibody Drug

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 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 Influence of disulfide bond isoforms on drug conjugation sites in cysteine-linked IgG2 antibody-drug conjugates

mAbs ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 583-595 ◽  
Author(s):  
Lily Liu-Shin ◽  
Adam Fung ◽  
Arun Malhotra ◽  
Gayathri Ratnaswamy
Keyword(s):  
Disulfide Bond ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Igg2 Antibody ◽  
Antibody Drug

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.

Impact of Drug Conjugation on Pharmacokinetics and Tissue Distribution of Anti-STEAP1 Antibody–Drug Conjugates in Rats

2011 ◽  
Vol 22 (10) ◽  
pp. 1994-2004 ◽  
Author(s):  
C. Andrew Boswell ◽  
Eduardo E. Mundo ◽  
Crystal Zhang ◽  
Daniela Bumbaca ◽  
Nicole R. Valle ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Antibody Drug

Convergent synthesis of hydrophilic monomethyl dolastatin 10 based drug linkers for antibody–drug conjugation

2019 ◽  
Vol 17 (35) ◽  
pp. 8115-8124 ◽  
Author(s):  
Kanwen Yang ◽  
Bo Chen ◽  
Diego A. Gianolio ◽  
James E. Stefano ◽  
Michelle Busch ◽  
...  
Keyword(s):  
Convergent Synthesis ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Hydrophilic Drug ◽  
Free Antibody ◽  
Antibody Drug ◽  
Dolastatin 10

A cytotoxic reagent-free fragment coupling methodology was developed to produce hydrophilic drug linkers to prepare aggregation free antibody–drug conjugates.

scholarly journals Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hung-Ju Hsu ◽  
Chao-Ping Tung ◽  
Chung-Ming Yu ◽  
Chi-Yung Chen ◽  
Hong-Sen Chen ◽  
...  
Keyword(s):  
Cancer Therapeutics ◽  
Tumor Xenograft ◽  
Pancreatic Tumors ◽  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Synthetic Antibody ◽  
Drug Conjugates ◽  
Xenograft Models ◽  
Antibody Drug

AbstractMesothelin (MSLN) is an attractive candidate of targeted therapy for several cancers, and hence there are increasing needs to develop MSLN-targeting strategies for cancer therapeutics. Antibody–drug conjugates (ADCs) targeting MSLN have been demonstrated to be a viable strategy in treating MSLN-positive cancers. However, developing antibodies as targeting modules in ADCs for toxic payload delivery to the tumor site but not to normal tissues is not a straightforward task with many potential hurdles. In this work, we established a high throughput engineering platform to develop and optimize anti-MSLN ADCs by characterizing more than 300 scFv CDR-variants and more than 50 IgG CDR-variants of a parent anti-MSLN antibody as candidates for ADCs. The results indicate that only a small portion of the complementarity determining region (CDR) residues are indispensable in the MSLN-specific targeting. Also, the enhancement of the hydrophilicity of the rest of the CDR residues could drastically increase the overall solubility of the optimized anti-MSLN antibodies, and thus substantially improve the efficacies of the ADCs in treating human gastric and pancreatic tumor xenograft models in mice. We demonstrated that the in vivo treatments with the optimized ADCs resulted in almost complete eradication of the xenograft tumors at the treatment endpoints, without detectable off-target toxicity because of the ADCs’ high specificity targeting the cell surface tumor-associated MSLN. The technological platform can be applied to optimize the antibody sequences for more effective targeting modules of ADCs, even when the candidate antibodies are not necessarily feasible for the ADC development due to the antibodies’ inferior solubility or affinity/specificity to the target antigen.

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