scholarly journals Antibody‐Drug‐Conjugate MORAb‐202 exhibits long‐lasting antitumor efficacies against TNBC PDx Models

2021 ◽  
Author(s):  
Keiji Furuuchi ◽  
Katherine Rybinski ◽  
James Fulmer ◽  
Tomoyuki Moriyama ◽  
Brian Drozdowski ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Pdx Models ◽  
Antibody Drug

scholarly journals LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 757 ◽  
Author(s):  
Eytan Ben-Ami ◽  
Raul Perret ◽  
Ying Huang ◽  
Félicie Courgeon ◽  
Prafulla C. Gokhale ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Stromal Cells ◽  
Soft Tissue Sarcomas ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
In Vivo Experiments ◽  
Patient Derived Xenograft ◽  
Pdx Models ◽  
Antibody Drug

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other 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.

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