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. 

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 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.

scholarly journals Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1

2021 ◽  
Vol 9 (8) ◽  
Author(s):  
Mony Ung ◽  
Jean Lacaze ◽  
Eleonora Maio ◽  
Florence Dalenc
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
Bystander Effect ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising. Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.

scholarly journals Clinical pharmacology of vc-MMAE antibody–drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies

mAbs ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 1699768 ◽  
Author(s):  
Chunze Li ◽  
Cindy Zhang ◽  
Zao Li ◽  
Divya Samineni ◽  
Dan Lu ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Cancer Patients ◽  
Phase 1 ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

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 Antibody-drug Conjugates with Novel Kinesin Spindle Protein Inhibitor Payloads and a Tailor-made Linker Chemistry

2019 ◽  
Author(s):  
Hans-Georg Hans-Georg Lerchen ◽  
Beatrix Stelte-Ludwig ◽  
Anette Sommer ◽  
Sandra Berndt ◽  
Dennis Kirchhoff ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Patients ◽  
Therapeutic Window ◽  
Protein Inhibitor ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Kinesin Spindle Protein ◽  
Antibody Drug

With the approval of meanwhile five ADCs and more than 80 ADCs in clinical trials, the ADC landscape has developed rapidly during the last decade. However, as indicated also by the large number of ADCs which failed in the clinic, it remains challenging to achieve a sufficiently large therapeutic window in cancer patients.

scholarly journals Treating Prostate Cancer by Antibody–Drug Conjugates

2021 ◽  
Vol 22 (4) ◽  
pp. 1551
Author(s):  
Matteo Rosellini ◽  
Matteo Santoni ◽  
Veronica Mollica ◽  
Alessandro Rizzo ◽  
Alessia Cimadamore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Male Population ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Castration Resistant ◽  
Antibody Drug

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

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

2021 ◽  
Vol 12 (1) ◽  
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 inflammatory response, 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 xenograft mouse models 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.

ASCO-GU 2019: Metastasierte Urothelkarzinome

2019 ◽  
Vol 10 (03) ◽  
pp. 140-141
Author(s):  
Alexander Kretzschmar
Keyword(s):  
San Francisco ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Chapel Hill ◽  
Antibody Drug

Die Therapielandschaft des metastasierten Urothelkarzinoms hat sich seit der Zulassung der ersten Immun-Checkpoint-Inhibitoren verändert. Die neuen Therapien sind deutlich effektiver, allerdings erreichen die Responseraten der neuen Therapien nur bis zu etwa 30 %, beklagte Prof. Matthew Milowsky, Chapel Hill/USA, auf einer Oral Abstract Session auf dem ASCO-GU. In San Francisco gaben erste Vorträge und Poster bereits einen Einblick, wovon diejenigen Patienten profitieren könnten, die auf die etablierten Chemotherapien und die neuen Immuntherapien nicht ansprechen. Manche Onkologen sprechen bereits von der „Post-Checkpoint-Ära”. Als Kandidaten werden vor allem Antikörper-Wirkstoff-Konjugate (antibody-drug conjugates; ADC) gehandelt – und zwar nicht nur zur Therapie des metastasierten Blasenkarzinoms.

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