Author: Glazer, Peter M. ; Krysztofiak, Adam ; Rackear, Madison ; Abdullah, Rashed ; Liu, Yanfeng ; Ludwig, Dale L. ; Rogers, Faye A. ; Bleichert, Franziska ; Ianniello, Zaira ; Colón-Ríos, Daniel A. ; Dwivedi, Rohini ; Quijano, Elias

Monoclonal antibody therapies for cancer have demonstrated extraordinary clinical success in recent years. However, these strategies are thus far mostly limited to specific cell surface antigens, even though many disease targets are found intracellularly. Here we report studies on the humanization of a full-length, nucleic acid binding, monoclonal lupus-derived autoantibody, 3E10, which exhibits a novel mechanism of cell penetration and tumor specific targeting. Comparing humanized variants of 3E10, we demonstrate that cell uptake depends on the nucleoside transporter ENT2, and that faster cell uptake and superior in vivo tumor targeting are associated with higher affinity nucleic acid binding. We show that one human variant retains the ability of the parental 3E10 to bind RAD51, serving as a synthetically lethal inhibitor of homology-directed repair in vitro. These results provide the basis for the rational design of a novel antibody platform for therapeutic tumor targeting with high specificity following systemic administration.

01 Feb 2024·Virus Research

New anti-SARS-CoV-2 aminoadamantane compounds as antiviral candidates for the treatment of COVID-19

Article

Author: Barbosa-Stancioli, Edel Figueiredo ; de Almeida, Isabela Neves ; Coêlho Maciel, Mariella Sousa ; Andrade, Luis Adan Flores ; Serafim, Mateus Sá Magalhães ; Lopes-Ribeiro, Ágata ; De Fátima, Ângelo ; Barreto, Luiza Valença ; Corrêa-Dias, Laura Cardoso ; Guatimosim, Silvia Carolina ; Coelho-Dos-Reis, Jordana Grazziela Alves ; Moraes, Thaís de Fátima Silva ; Silva, Mário Morais ; Tsuji, Moriya ; de Almeida Marques, Daisymara Priscila ; Ferreira, Rafaela Salgado ; Reis, Erik Vinicius Sousa ; da Fonseca, Flávio Guimarães ; Lourenço, Karine Lima ; de Oliveira, Leonardo Camilo ; Litwinski, Vivian Costa Vasconcelos ; Maltarollo, Vinicius Gonçalves ; Costa, Nathália Evelyn Morais ; De Barros, Wellington Alves ; Andrade, Lídia Maria de ; Clarindo, Felipe Alves ; Arantes, Thalita Souza

Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells up to a concentration of 1,000 µM. The inhibitory concentration (IC₅₀) of aminoadamantane was 39.71 µM in Vero CCL-81 cells and the derivatives showed significantly lower IC₅₀ values, especially for compounds 3F4 (0.32 µM), 3F5 (0.44 µM) and 3E10 (1.28 µM). Additionally, derivatives 3F5 and 3E10 statistically reduced the fluorescence intensity of SARS-CoV-2 protein S from Vero cells at 10 µM. Transmission microscopy confirmed the antiviral activity of the compounds, which reduced cytopathic effects induced by the virus, such as vacuolization, cytoplasmic projections, and the presence of myelin figures derived from cellular activation in the face of infection. Additionally, it was possible to observe a reduction of viral particles adhered to the cell membrane and inside several viral factories, especially after treatment with 3F4. Moreover, although docking analysis showed favorable interactions in the catalytic site of Cathepsin L, the enzymatic activity of this enzyme was not inhibited significantly in vitro. The new derivatives displayed lower predicted toxicities than aminoadamantane, which was observed for either rat or mouse models. Lastly, in vivo antiviral assays of aminoadamantane derivatives in BALB/cJ mice after challenge with the mouse-adapted strain of SARS-CoV-2, corroborated the robust antiviral activity of 3F4 derivative, which was higher than aminoadamantane and its other derivatives. Therefore, aminoadamantane derivatives show potential broad-spectrum antiviral activity, which may contribute to COVID-19 treatment in the face of emerging and re-emerging SARS-CoV-2 variants of concern.

01 Apr 2023·Sensors and Actuators B: Chemical

Development of nucleocapsid-specific monoclonal antibodies for SARS-CoV-2 and their ELISA diagnostics on an automatic microfluidic device

Article

Author: Nguyen, Hau Van ; Phan, Vu Minh ; Lim, Won-Hee ; Cho, Eun-Wie ; Seo, Tae Seok ; Yang, Jihyun ; Poo, Haryoung ; Heo, Chang-Kyu

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has threatened public health globally, and the emergence of viral variants has exacerbated an already precarious situation. To prevent further spread of the virus and determine government action required for virus control, accurate and rapid immunoassays for SARS-CoV-2 diagnosis are urgently needed. In this study, we generated monoclonal antibodies (mAbs) against the SARS-CoV-2 nucleocapsid protein (NP), compared their reactivity using an enzyme-linked immunosorbent assay (ELISA), and selected four mAbs designated 1G6, 3E10, 3F10, and 5B6 which have higher reactivity to NP and viral lysates of SARS-CoV-2 than other mAbs. Using an epitope mapping assay, we identified that 1G6 detected the C-terminal domain of SARS-CoV-2 NP (residues 248-364), while 3E10 and 3F10 bound to the N-terminal domain (residues 47-174) and 3F10 detected the N-arm region (residues 1-46) of SARS-CoV-2 NP. Based on the epitope study and sandwich ELISA, we selected the 1G6 and 3E10 Abs as an optimal Ab pair and applied them for a microfluidics-based point-of-care (POC) ELISA assay to detect the NPs of SARS-CoV-2 and its variants. The integrated and automatic microfluidic system could operate the serial injection of the sample, the washing solution, the HRP-conjugate antibody, and the TMB substrate solution simply by controlling air purge via a single syringe. The proposed Ab pair-equipped microsystem effectively detected the NPs of SARS-CoV-2 variants as well as in clinical samples. Collectively, our proposed platform provides an advanced protein-based diagnostic tool for detecting SARS-CoV-2.

100 Deals associated with Deoxymab

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Cancer	Phase 1	-	Mereo BioPharma 5, Inc.	-
Pancreatic Cancer	Phase 1	-	Patrys Ltd.	-
Pancreatic Cancer	Phase 1	-	Yale University	-
Systemic Lupus Erythematosus	Phase 1	-	Yale University	-
Systemic Lupus Erythematosus	Phase 1	-	Mereo BioPharma 5, Inc.	-
Systemic Lupus Erythematosus	Phase 1	-	Patrys Ltd.	-
Neoplasms	Preclinical	US	Yale University	01 Jul 2017

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