scholarly journals Site-selective modification strategies in antibody–drug conjugates

2021 ◽  
Author(s):  
Stephen J. Walsh ◽  
Jonathan D. Bargh ◽  
Friederike M. Dannheim ◽  
Abigail R. Hanby ◽  
Hikaru Seki ◽  
...  
Keyword(s):  
Cell Types ◽  
Specific Cell ◽  
Antibody Drug Conjugates ◽  
Specific Targeting ◽  
Drug Conjugates ◽  
Site Selective ◽  
Antibody Drug ◽  
Made In

Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. This review summarises the advances made in the construction of homogenous ADCs.

ChemInform Abstract: Construction of Homogeneous Antibody-Drug Conjugates Using Site-Selective Protein Chemistry

ChemInform ◽  
2016 ◽  
Vol 47 (25) ◽  
Author(s):  
Padma Akkapeddi ◽  
Saara-Anne Azizi ◽  
Allyson M. Freedy ◽  
Pedro M. S. D. Cal ◽  
Pedro M. P. Gois ◽  
...  
Keyword(s):  
Protein Chemistry ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Site Selective ◽  
Antibody Drug

scholarly journals A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody–drug conjugates

2019 ◽  
Vol 10 (3) ◽  
pp. 694-700 ◽  
Author(s):  
Stephen J. Walsh ◽  
Soleilmane Omarjee ◽  
Warren R. J. D. Galloway ◽  
Terence T.-L. Kwan ◽  
Hannah F. Sore ◽  
...  
Keyword(s):  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Native Proteins ◽  
Site Selective ◽  
Antibody Drug

Divinylpyrimidine (DVP) linkers enable access to highly stable and functional antibody–drug conjugates.

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 Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers

2021 ◽  
Author(s):  
Haiyong Peng
Keyword(s):  
Cancer Therapy ◽  
Small Molecules ◽  
Pharmaceutical Companies ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Solid Malignancies ◽  
Selective Delivery ◽  
And Performance ◽  
Antibody Drug ◽  
Made In

Abstract Antibody–drug conjugates (ADCs) are targeted therapeutics generated by conjugation of cytotoxic small molecules to monoclonal antibodies (mAbs) via chemical linkers. Due to their selective delivery of toxic payloads to antigen-positive cancer cells, ADCs demonstrate wider therapeutic indexes compared to conventional chemotherapy. After decades of intensive research and development, significant advances have been made in the field, leading to a total of ten FDA-approved ADCs to treat cancer patients. Currently, ~ 80 ADCs targeting different antigens are under clinical evaluation for treatment of either hematological or solid malignancies. Notably, 3 ADCs targeting the same oncofetal protein, ROR1, have attracted considerable attention when they were acquired or licensed successively in the fourth quarter of 2020 by 3 major pharmaceutical companies. Apparently, ROR1 has emerged as an attractive target for cancer therapy. Since all the components of ADCs, including the antibody, linker, and payload, as well as the conjugation method, play critical roles in ADC’s efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

scholarly journals Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

2020 ◽  
Author(s):  
Chisato M. Yamazaki ◽  
Aiko Yamaguchi ◽  
Yasuaki Anami ◽  
Wei Xiong ◽  
Yoshihiro Otani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Breast Tumor ◽  
Tumor Heterogeneity ◽  
Chemotherapeutic Agents ◽  
Specific Cell ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Dual Drug ◽  
Antibody Drug

ABSTRACTBreast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal immunogenicity, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in a xenograft mouse model representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.

scholarly journals Clinical Activity of Anti-HER2-Antibody Drug Conjugates in HER2-Mutated Metastatic Cancer Patients

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Albert J. Brougham ◽  
Jeffrey Solzak ◽  
Milan Radovich
Keyword(s):  
Cancer Patients ◽  
Metastatic Cancer ◽  
Clinical Activity ◽  
Specific Cell ◽  
Cell Surface Antigens ◽  
Antibody Drug Conjugates ◽  
Activating Mutations ◽  
Drug Conjugates ◽  
Tumor Types ◽  
Antibody Drug

Background/Objective: Antibody drug conjugates (ADCs) deliver potent cytotoxic therapy in a highly targeted manner by binding cancer-specific cell surface antigens. HER2 is a receptor tyrosine kinase that is commonly amplified in breast and gastric cancers, but more recently has been shown to harbor gain-of-function activating mutations in several cancer types. Recent observations have suggested that HER2-ADCs may be viable therapies for patients that harbor these activating mutations. This research retrospectively explores the efficacy of HER2-ADCs in metastatic cancer patients in a real-world setting. Methods: Patient information was gathered from the Precision Genomics program at IU Health, narrowed for specific mutation criteria (HER2 pathogenic mutation), cross referenced with OncoKB to legitimize oncogenicity, and selected for patients prescribed HER2-ADCs. For these patients, pre-treatment and mid-treatment CT-scans were analyzed following RECIST protocols. The primary outcomes were overall response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Secondary outcomes were to tabulate the frequency and clinical characteristics of HER2-mutated tumors. Results: Out of 517 patients with somatic HER2 mutations, 60 patients had a pathogenic HER2 mutation. Of these 60 patients, the most common tumor types were 26.67% Breast and 11.67% Bladder/Urothelial. 11 of 60 patients were prescribed a HER2-ADC (Trastuzumab Emtansine = 10, Trastuzumab Deruxtecan = 1). 8 of 11 patients were evaluable for response with RECIST criteria with 1 patient having a partial response, 4 patients having stable disease and 3 patients having progressive disease. ORR=13%, CBR=63%, Median PFS = 2.77 months (95% CI: 2.15-3.39 months). Conclusion/Implications: To our knowledge, this is the first report of HER2-ADCs demonstrating clinical activity in HER2-mutated cancers across tumor types. Further clinical trials are ongoing that will validate these initial findings. 

scholarly journals Correction: A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody–drug conjugates

2019 ◽  
Vol 10 (2) ◽  
pp. 633-634
Author(s):  
Stephen J. Walsh ◽  
Soleilmane Omarjee ◽  
Warren R. J. D. Galloway ◽  
Terence T.-L. Kwan ◽  
Hannah F. Sore ◽  
...  
Keyword(s):  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Native Proteins ◽  
Site Selective ◽  
Antibody Drug

Correction for ‘A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody–drug conjugates’ by Stephen J. Walsh et al., Chem. Sci., 2019, DOI: 10.1039/c8sc04645j.

scholarly journals Construction of homogeneous antibody–drug conjugates using site-selective protein chemistry

2016 ◽  
Vol 7 (5) ◽  
pp. 2954-2963 ◽  
Author(s):  
Padma Akkapeddi ◽  
Saara-Anne Azizi ◽  
Allyson M. Freedy ◽  
Pedro M. S. D. Cal ◽  
Pedro M. P. Gois ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Protein Chemistry ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Drug Conjugation ◽  
Selective Chemical ◽  
Site Selective ◽  
Antibody Drug

The use of site-selective chemical drug-conjugation strategies enables the construction of antibody–drug conjugates (ADCs) with superior therapeutic efficacy.”

scholarly journals Site-selective lysine conjugation methods and applications towards antibody–drug conjugates

2021 ◽  
Author(s):  
Muhammed Haque ◽  
Nafsika Forte ◽  
James R. Baker
Keyword(s):  
Recent Work ◽  
Feature Article ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Lysine Modification ◽  
Site Selective ◽  
Antibody Drug

In this feature article we discuss developments in site-selective lysine modification methodologies and their application towards the synthesis of antibody–drug conjugates; including our recent work on a cysteine-to-lysine transfer (CLT) protocol.

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