Cancer-targeting Antibody–Drug Conjugates: Site-specific Conjugation of Doxorubicin to Anti-EGFR 528 Fab' through a Polyethylene Glycol Linker

2011 ◽  
Vol 64 (6) ◽  
pp. 779 ◽  
Author(s):  
Lisa P. T. Hong ◽  
Judith A. Scoble ◽  
Larissa Doughty ◽  
Gregory Coia ◽  
Charlotte C. Williams
Keyword(s):  
Polyethylene Glycol ◽  
Growth Factor Receptor ◽  
Antibody Fragment ◽  
Aqueous Solubility ◽  
Cancer Targeting ◽  
Antibody Activity ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Epidermal Growth ◽  
Antibody Drug

Antibody–drug conjugates have been prepared to examine the effect that attaching small-molecule drugs to an antibody fragment has on antibody activity. The anticancer drug doxorubicin was covalently attached through a polyethylene glycol linker to a cancer-targeting, anti-epidermal growth factor receptor antibody fragment (Fab′). The reactivity of maleimide was compared with a substituted maleimide derivative (citraconimide) in conjugation reactions with cysteine residues on a Fab′. Introduction of polyethylene glycol increased aqueous solubility of the cytotoxic drug, which led to an improvement in overall yield of the conjugation reaction with the antibody fragment. Antibody–drug conjugates prepared retained activity of the parent antibody, as determined by antigen binding experiments measured by surface plasmon resonance.

Monoclonal antibodies, small molecule inhibitors and antibody-drug conjugates as HER2 inhibitors

2020 ◽  
Vol 27 ◽  
Author(s):  
Xiu-Fang Li ◽  
Chen-Fu Liu ◽  
Guo-Wu Rao
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Growth Factor Receptor ◽  
Research Progress ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Her 2 ◽  
Epidermal Growth ◽  
Antibody Drug

: Overexpression of human epidermal growth factor receptor (HER)-2 is found in a variety of cancers, often portending poor clinical outcomes. Therefore, HER2 is an attractive target for treatment. This review describes the research progress of HER2 targeted inhibitors in recent years. Excellent reviews are available, so we focus on the development, mechanisms of action, and structure-activity relationships of different types of inhibitors, including monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs). In addition, the differences among them are compared.

scholarly journals Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 400 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hisato Kawakami
Keyword(s):  
Gastroesophageal Junction ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Gastroesophageal Junction Cancer ◽  
Development Of Resistance ◽  
Epidermal Growth ◽  
Antibody Drug

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

scholarly journals Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6752 ◽  
Author(s):  
Zhefu Dai ◽  
Xiao-Nan Zhang ◽  
Fariborz Nasertorabi ◽  
Qinqin Cheng ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Reaction Times ◽  
Single Step ◽  
Her2 Positive ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

What Can We Learn about Antibody-Drug Conjugates from the T-DM1 Experience?

2015 ◽  
pp. e117-e125 ◽  
Author(s):  
Francisco J. Esteva ◽  
Kathy D. Miller ◽  
Beverly A. Teicher
Keyword(s):  
Small Molecule ◽  
Antibody Fragment ◽  
Cytotoxic Agents ◽  
Specific Cell ◽  
Malignant Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Protein Toxin ◽  
Antibody Conjugates ◽  
Antibody Drug

Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation. Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment–protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates, and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40 antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for patients with cancer.

scholarly journals HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

2019 ◽  
Author(s):  
Gabriel Rinnerthaler ◽  
Simon Peter Gampenrieder ◽  
Richard Greil
Keyword(s):  
Kinase Inhibitors ◽  
Clinical Investigation ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Oncogenic Driver ◽  
Antibody Drug

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has increased meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

scholarly journals HER2-/HER3-Targeting Antibody—Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1047
Author(s):  
Kimio Yonesaka
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Drug Conjugates ◽  
Epidermal Growth ◽  
Antibody Drug

Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including secondary EGFR-mutation and its downstream RAS/RAF mutation. Since the discovery of the role of human epidermal growth factor receptor 2 (HER2) and HER3 in drug resistance, HER2- or HER3-targeting treatment strategies using monoclonal antibodies have been intensively examined and have demonstrated impressive responsiveness and limitations. Finally, an innovative targeted therapy called antibody drug conjugates (ADC) has provided a solution to overcome this resistance. Specifically, a new cleavable linker-payload system enables stable drug delivery to cancer cells, causing selective destruction. HER2-targeting ADC trastuzumab deruxtecan demonstrated promising responsiveness in patients with HER2-positive CRC, in a phase 2 clinical trial (objective response rate = 45.3%). Furthermore, HER3-targeting patritumab deruxtecan, another ADC, exhibited impressive tumor shrinkage in pretreated patients with EGFR-mutated NSCLC, in a phase 1 clinical trial. This manuscript presents an overview of the accumulated evidence on HER2- and HER3-targeting therapy, especially ADCs, and discussion of remaining issues for further improving these treatments in cancers resistant to EGFR inhibitors.

A novel self-assembled pH-sensitive targeted nanoparticle platform based on antibody–4arm-polyethylene glycol–pterostilbene conjugates for co-delivery of anticancer drugs

2018 ◽  
Vol 6 (4) ◽  
pp. 656-665 ◽  
Author(s):  
Ke-Feng Liu ◽  
Yan-Xue Liu ◽  
Lin Dai ◽  
Chun-Xiao Li ◽  
Luying Wang ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Cancer Immunotherapy ◽  
Anticancer Drugs ◽  
Targeted Delivery ◽  
Ph Sensitive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Self Assembled ◽  
Antibody Drug

Recently, antibody–drug conjugates (ADC) have shown potential for cancer immunotherapy by tumor-targeted delivery of anticancer drugs.

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