scholarly journals Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate

Oncotarget ◽  
2017 ◽  
Vol 8 (15) ◽  
pp. 25080-25096 ◽  
Author(s):  
Mohammed Adil Butt ◽  
Hayley Pye ◽  
Rehan J. Haidry ◽  
Dahmane Oukrif ◽  
Saif-U-Rehman Khan ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Mucin Glycoprotein ◽  
Antibody Drug

scholarly journals ROR1 targeting with the antibody drug-conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models

Blood ◽  
2021 ◽  
Author(s):  
Tiziana Vaisitti ◽  
Francesca Arruga ◽  
Nicoletta Vitale ◽  
Thanh-Trang Thi Lee ◽  
Mira Ko ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Lymphocytic Leukemia ◽  
Orphan Receptor ◽  
Aggressive Lymphoma ◽  
Tumor Cell Death ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Richter Syndrome ◽  
Hematological Cancers ◽  
Antibody Drug

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on normal adult tissues, making it an attractive, tumor-specific therapeutic target. VLS‑101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC‑961 (a humanized immunoglobulin IgG1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate (mc-vc-PAB) linker, and the anti‑microtubule cytotoxin monomethyl auristatin E (MMAE). VLS‑101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS‑PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the post-therapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A Phase 1 clinical trial of VLS‑101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.

Computational Approaches in Antibody-drug Conjugate Optimization for Targeted Cancer Therapy

2018 ◽  
Vol 18 (13) ◽  
pp. 1091-1109 ◽  
Author(s):  
Rita Melo ◽  
Agostinho Lemos ◽  
Antonio J. Preto ◽  
Jose G. Almeida ◽  
Joao D.G. Correia ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Coarse Grained ◽  
Cytotoxic Agent ◽  
Target Cells ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Cross Correlation Analysis ◽  
Traditional Therapies ◽  
Modular Structures ◽  
Antibody Drug

Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second- and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.

scholarly journals An antibody-drug conjugate with intracellular drug release properties showing specific cytotoxicity against CD7-positive cells

2021 ◽  
pp. 106626
Author(s):  
Jing Zhang ◽  
Arvind Jain ◽  
Sabine Milhas ◽  
Daniel J. Williamson ◽  
Justyna Mysliwy ◽  
...  
Keyword(s):  
Drug Release ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Specific Cytotoxicity ◽  
Antibody Drug
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