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.

scholarly journals Factors Affecting the Pharmacology of Antibody–Drug Conjugates

Antibodies ◽  
2018 ◽  
Vol 7 (1) ◽  
pp. 10 ◽  
Author(s):  
Andrew Lucas ◽  
Lauren Price ◽  
Allison Schorzman ◽  
Mallory Storrie ◽  
Joseph Piscitelli ◽  
...  
Keyword(s):  
Factors Affecting ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
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.

scholarly journals Therapeutic potential of nimotuzumab PEGylated-maytansine antibody drug conjugates against EGFR positive xenograft

Oncotarget ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 1031-1044 ◽  
Author(s):  
Siddesh V. Hartimath ◽  
Ayman El-Sayed ◽  
Amal Makhlouf ◽  
Wendy Bernhard ◽  
Carolina Gonzalez ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

2021 ◽  
Author(s):  
Yasuaki Anami ◽  
Yoshihiro Otani ◽  
Wei Xiong ◽  
Summer Y. Y. Ha ◽  
Aiko Yamaguchi ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Antitumor Effects ◽  
Antibody Drug Conjugates ◽  
Cancer Management ◽  
Drug Conjugates ◽  
Therapeutic Benefits ◽  
Antibody Drug

Glioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.

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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