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.

scholarly journals An antibody drug conjugate targeting a GSTA glycosite-signature epitope of mucin1 expressed by non-small cell lung cancer

2019 ◽  
Author(s):  
Deng Pan ◽  
Yubo Tang ◽  
Jiao Tong ◽  
Chengmei Xie ◽  
Jiaxi Chen ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Tumor Xenograft ◽  
Live Cells ◽  
Nsclc Cell Line ◽  
Mouse Tumor ◽  
Antibody Drug Conjugate ◽  
Multiple Cancer ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

AbstractBackgroundAntibodies targeting abnormally glycosylated proteins have been ineffective in treating cancer. Antibody-drug conjugates are emerging as an efficient option, which allow specific delivery of drugs into tumors. We and others have dissected the abnormally glycosylated tandem repeat region of MUC1 glycoprotein as three site-specific glycosylated neoantigen peptide motifs (PDTR, GSTA, GVTS) for monoclonal antibody binding.MethodsInternalization of monoclonal antibodies was studied by immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples were studied by immunohistochemistry. The efficacy of anti-MUC1 ADCs were evaluated with various cancer cell lines and mouse tumor xenograft model.ResultsWe describe an anti-MUC1 ADC by conjugating GSTA neoantigen-specific 16A with monomethyl auristatin E (MMAE). 16A-MMAE showed potent antitumoral efficacy with IC50 ranging from 0.2 to 49.4 nM toward multiple types of cancer cells. In vivo, 16A-MMAE showed dose-dependent inhibition of tumor growth in mouse xenograft of NCI-H838 NSCLC cell line, with minimum effective dose at 1 mg/kg. At the dose of 3 mg/kg, 16A-MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1.ConclusionsThe high antitumoral efficacy of 16A-MMAE suggest that aberrant glycosylated MUC1 neoantigen is a target with high positivity in multiple cancer types for ADC development. Personalized therapy may be achieved by development of glycosite-specific antibody-drug conjugates.

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 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 Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

2019 ◽  
Vol 13 (9) ◽  
pp. 1855-1873 ◽  
Author(s):  
Yiran Tao ◽  
Ruixue Wang ◽  
Qinhuai Lai ◽  
Mengdan Wu ◽  
Yuxi Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Colon Carcinoma ◽  
Antitumor Effects ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Antibody-Drug Conjugates Targeting the Urokinase Receptor (uPAR) as a Possible Treatment of Aggressive Breast Cancer

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 54 ◽  
Author(s):  
Efrat T. Harel ◽  
Penelope M. Drake ◽  
Robyn M. Barfield ◽  
Irene Lui ◽  
Shauna Farr-Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Regression ◽  
Recombinant Antibody ◽  
Xenograft Model ◽  
Urokinase Receptor ◽  
Stable Complex ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Mouse Xenograft Model ◽  
Antibody Drug

A promising molecular target for aggressive cancers is the urokinase receptor (uPAR). A fully human, recombinant antibody that binds uPAR to form a stable complex that blocks uPA-uPAR interactions (2G10) and is internalized primarily through endocytosis showed efficacy in a mouse xenograft model of highly aggressive, triple negative breast cancer (TNBC). Antibody-drug conjugates (ADCs) of 2G10 were designed and produced bearing tubulin inhibitor payloads ligated through seven different linkers. Aldehyde tag technology was employed for linking, and either one or two tags were inserted into the antibody heavy chain, to produce site-specifically conjugated ADCs with drug-to-antibody ratios of either two or four. Both cleavable and non-cleavable linkers were combined with two different antimitotic toxins—MMAE (monomethylauristatin E) and maytansine. Nine different 2G10 ADCs were produced and tested for their ability to target uPAR in cell-based assays and a mouse model. The anti-uPAR ADC that resulted in tumor regression comprised an MMAE payload with a cathepsin B cleavable linker, 2G10-RED-244-MMAE. This work demonstrates in vitro activity of the 2G10-RED-244-MMAE in TNBC cell lines and validates uPAR as a therapeutic target for TNBC.

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