Delving into the Latest Updates on Tezatabep Matraxetan with Synapse

Overview

Basic Info

Drug Type

Peptide Conjugate Radionuclide, Diagnostic radiopharmaceuticals

Synonyms

Anti-HER2 Affibody, Anti-HER2 small molecule imaging agent (Affibody), Tezatabep Matraxetan

+ [5]

Target

HER2

Mechanism

HER2 modulators(Receptor protein-tyrosine kinase erbB-2 modulators)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesDigestive System Disorders+ [1]

Active Indication

Gastrooesophageal junction cancerHER2 Positive Breast CancerNon-Small Cell Lung Cancer

Inactive Indication

Metastatic breast cancer

Originator Organization

Affibody AB

Active Organization

Affibody Medical AB

Inactive Organization

Affibody AB

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

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Gene Sequence

Sequence Code 171583

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Kawasaki disease (KD) is a disease characterized by systemic immune vasculitis that often involves coronary arteries and can result in long-term cardiovascular sequelae. Different strategies for treatment of KD-and KD-induced coronary artery lesions are currently under investigation, including passive immunization with anti-TNFα monoclonal antibodies (mAbs). Herein, we examine the potential therapeutic capabilities of a novel type of TNFα-targeting agent based on an affibody molecule possessing fundamentally different properties than mAbs. Using phage display technology, we successfully screened and obtained three TNF-α binding affibody molecules and confirmed their high binding affinity and specificity for recombinant and native TNF-α by surface plasmon resonance (SPR), confocal double immunofluorescence and coimmunoprecipitation assays. Moreover, by binding to TNF-α, the affibody molecules could effectively neutralize TNFα-induced L929 cytotoxicity. To increase the targeting properties and serum half-life, one preferred affibody molecule Z_TNF-α263 was redesigned to assemble drugs with bivalent TNFα binding with added specificity for serum albumin (Z_TNF-α263-ABD₀₃₅-Z_TNF-α263, hereinafter denoted ZTAT). We further determined its binding ability, TNF-α signal blocking and neutralizing capacity, serum half-life and immunogenicity. Most importantly, our study provides strong evidence that the engineered ZTAT protein was therapeutically effective against KD induced-endothelial injury, as judged by both in vitro and in vivo assessments. These data suggested that because of the flexibility inherent, low-molecular weight anti-TNFα affibody construct ZTAT, can be developed into a potent therapeutic agent that can be produced and purified cost-effectively.

11 Oct 2024·ACS Pharmacology & Translational Science

Affibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor-3 Demonstrate Therapeutic Efficacy in Mice Bearing Low Expressing Xenografts

Article

Author: Löfblom, John ; Yin, Wen ; Björklund, Elvira ; Rinne, Sara S. ; Zhang, Jie ; Leitao, Charles Dahlsson ; Gräslund, Torbjörn ; Ståhl, Stefan ; Abouzayed, Ayman ; Vorobyeva, Anzhelika ; Orlova, Anna

The outcome of clinical trials evaluating drugs targeting the human epidermal growth factor receptor 3 (HER3) has been poor, with primary concerns related to lack of efficacy. HER3 is considered a difficult target since its overexpression on tumors is relatively low and there is normal expression in many different organs. However, a significant number of patients across different cancer indications have overexpression of HER3 and the development of novel modalities targeting HER3 is therefore warranted. Here, we have investigated the properties of affibody-based drug conjugates targeting HER3. The HER3-targeting affibody molecule Z_HER3 was fused in a mono- and bivalent format to an engineered albumin-binding domain (ABD) for in vivo half-life extension and was coupled to the cytotoxic drug DM1 via a non-cleavable maleimidocaproyl (mc) linker. In vivo, a moderate uptake was observed for [^99mTc]Tc-labeled Z_HER3-ABD-Z_HER3-mcDM1 in HER3 expressing BxPC3 tumors (3.5 ± 0.3%IA/g) at 24 h after injection, and clearance was predominately renal-mediated. Treatment of mice with BxPC3 human pancreatic cancer xenografts showed that a combination of Z_HER3-ABD-Z_HER3-mcDM1 and its cytostatic analog Z_HER3-ABD-Z_HER3 was efficacious and superior to treatment with only Z_HER3-ABD-Z_HER3, providing tumor growth inhibition and longer median survival (90 d) in comparison to monotherapy (68 d) and vehicle control (49 d). Z_HER3-ABD-Z_HER3-mcDM1 was found to be a potent drug conjugate for the treatment of HER3-expressing tumors in mice.

28 Aug 2024·Journal of the American Chemical Society

Integrating Dynamic Network Analysis with AI for Enhanced Epitope Prediction in PD-L1:Affibody Interactions

Article

Author: Nash, Michael A. ; Vanella, Rosario ; Yang, Byeongseon ; Bernardi, Rafael C. ; Gomes, Diego E. B.

Understanding binding epitopes involved in protein-protein interactions and accurately determining their structure are long-standing goals with broad applicability in industry and biomedicine. Although various experimental methods for binding epitope determination exist, these approaches are typically low throughput and cost-intensive. Computational methods have potential to accelerate epitope predictions; however, recently developed artificial intelligence (AI)-based methods frequently fail to predict epitopes of synthetic binding domains with few natural homologues. Here we have developed an integrated method employing generalized-correlation-based dynamic network analysis on multiple molecular dynamics (MD) trajectories, initiated from AlphaFold2Multimer structures, to unravel the structure and binding epitope of the therapeutic PD-L1:Affibody complex. Both AlphaFold2 and conventional molecular dynamics trajectory analysis were ineffective in distinguishing between two proposed binding models, parallel and perpendicular. However, our integrated approach, utilizing dynamic network analysis, demonstrated that the perpendicular mode was significantly more stable. These predictions were validated using a suite of experimental epitope mapping protocols, including cross-linking mass spectrometry and next-generation sequencing-based deep mutational scanning. Conversely, AlphaFold3 failed to predict a structure bound in the perpendicular pose, highlighting the necessity for exploratory research in the search for binding epitopes and challenging the notion that AI-generated protein structures can be accepted without scrutiny. Our research underscores the potential of employing dynamic network analysis to enhance AI-based structure predictions for more accurate identification of protein-protein interaction interfaces.

100 Deals associated with Tezatabep Matraxetan

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	NDA/BLA	SE	Affibody AB	01 Jun 2018
Metastatic breast cancer	NDA/BLA	SE	Affibody AB	01 Apr 2013
Gastrooesophageal junction cancer	Phase 2	SE	Affibody Medical AB	25 Aug 2022
HER2 Positive Breast Cancer	Phase 2	SE	Affibody Medical AB	25 Aug 2022
Non-Small Cell Lung Cancer	Phase 2	SE	Affibody Medical AB	25 Aug 2022