Delving into the Latest Updates on Sirtratumab Vedotin with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

sirtratumab vedotin

+ [5]

Target

SLITRK6 x Tubulin

Action

inhibitors

Mechanism

SLITRK6 inhibitors(SLIT and NTRK-like protein 6 inhibitors), Tubulin inhibitors

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Bladder Cancer

Inactive Indication

Metastatic urothelial carcinoma

Originator Organization

Agensys, Inc.

Active Organization

Agensys, Inc.

Seagen, Inc.

Inactive Organization

Astellas Pharma Global Development, Inc.

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC39H67N5O7

InChIKeyDASWEROEPLKSEI-UIJRFTGLSA-N

CAS Registry474645-27-7

View All Structures (2)

Boost your research with our ADC technology data.

login

or

view full example data

Boost your research with our ADC technology data.

Sequence Code 9509790L

Source: *****

Sequence Code 9509781H

Source: *****

AbstractTargeted payload delivery strategies, such as antibody‐drug conjugates (ADCs), have emerged as important therapeutics. Although considerable efforts have been made in the areas of antibody engineering and labeling methodology, improving the overall physicochemical properties of the linker/payload combination remains an important challenge. Here we report an approach to create an intrinsically hydrophilic linker domain. We find that benzyl α‐ammonium carbamates (BACs) undergo tandem 1,6–1,2‐elimination to release secondary amines. Using a fluorogenic hemicyanine as a model payload component, we show that a zwitterionic BAC linker improves labeling efficiency and reduces antibody aggregation when compared to a commonly used para‐amino benzyl (PAB) linker as well as a cationic BAC. Cellular and in vivo fluorescence imaging studies demonstrate that the model payload is specifically released in antigen‐expressing cells and tumors. The therapeutic potential of the BAC linker strategy was assessed using an MMAE payload, a potent microtubule‐disrupting agent frequently used for ADC applications. The BAC‐MMAE combination enhances labeling efficiency and cellular toxicity when compared to the routinely used PAB‐Val‐Cit ADC analogue. Broadly, this strategy provides a general approach to mask payload hydrophobicity and improve the properties of targeted agents.

01 Feb 2025·Tetrahedron

Drug-linker constructs bearing unique dual-mechanism tubulin binding payloads tethered through cleavable and non-cleavable linkers

Article

Author: VanNatta, Jennifer M ; Ford, Jacob W ; Pinney, Kevin G ; Trawick, Mary Lynn ; Hamel, Ernest ; Lin, Chen-Ming ; Bai, Ruoli ; Deng, Yuling ; Mondal, Deboprosad

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris^® (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).

15 Jan 2025·Bioconjugate Chemistry

Delivery of Monomethyl Auristatin F to the Tumor Microenvironment with Noninternalizing Fibroblast Activation Protein-Cleavable Small Molecule–Drug Conjugates Elicits Potent In Vivo Anticancer Activity

Article

Author: Bocci, Matilde ; Principi, Lucrezia ; Neri, Dario ; Gilardoni, Ettore ; Cazzamalli, Samuele ; Galbiati, Andrea

OncoFAP is an ultrahigh affinity ligand of fibroblast activation protein (FAP), a tumor-associated antigen overexpressed in the stroma of the majority of solid tumors. OncoFAP has been previously implemented as a tumor-homing moiety for the development of small molecule drug conjugates (SMDCs). In the same context, the glycine--proline dipeptide was included with the aim to selectively undergo cleavage only in the presence of the target FAP, triggering the consequent release of the cytotoxic payload in the tumor microenvironment. In this work, we evaluate the use of monomethyl auristatin F (MMAF) as a payload, a close derivative of MMAE bearing a charged carboxylic acid that hampers its cellular permeability, typically employed in the development of internalizing antibody-drug conjugates. The novel OncoFAP-GlyPro-MMAF and the previously described OncoFAP-GlyPro-MMAE were compared in a head-to-head therapeutic experiment in mice bearing FAP-positive tumors. Surprisingly, the MMAF conjugate mediated potent antitumor activity, despite its poor cellular permeability.

100 Deals associated with Sirtratumab Vedotin

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Bladder Cancer	Phase 1	-	Seagen, Inc.	-
Bladder Cancer	Phase 1	-	Agensys, Inc.	-
Metastatic urothelial carcinoma	Discovery	United States	Astellas Pharma Global Development, Inc.	14 Nov 2013
Metastatic urothelial carcinoma	Discovery	Canada	Seagen, Inc.	14 Nov 2013
Metastatic urothelial carcinoma	Discovery	Canada	Astellas Pharma Global Development, Inc.	14 Nov 2013
Metastatic urothelial carcinoma	Discovery	United States	Seagen, Inc.	14 Nov 2013
Bladder Cancer	Discovery	United States	-	-
Bladder Cancer	Discovery	Canada	-	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01963052 (Pubmed) Manual	Phase 1	Metastatic urothelial carcinoma SLITRK6	93	AGS15E	(iogtvtqtcl) = mibryymgog qzbbofwgxa (jamhnwxsst ) View more	Positive	05 Jan 2024
NCT01963052 (Pubmed) Manual	Phase 1	Metastatic urothelial carcinoma SLITRK6	93	AGS15E (with prior checkpoint inhibitor (CPI) therapy)	(yzrwdypwnq) = ijulzughao fjugpdocqj (ioixdchlij )	Positive	05 Jan 2024
NCT01963052 (ASCO2016)	Phase 1	Metastatic urothelial carcinoma	43	ASG-15ME	(tsvgrvibbh) = 95% of pts had adverse events (AEs) cyfkdsfkqv (qrtxrggnbw ) View more	Positive	20 May 2016

Login to view more data

Translational Medicine

Boost your research with our translational medicine data.

login

or

view full example data

Boost your research with our translational medicine data.

Deal

Boost your decision using our deal data.

login

or

view full example data

Boost your decision using our deal data.

Core Patent

Boost your research with our Core Patent data.

login

or

view full example data

Boost your research with our Core Patent data.

Clinical Trial

Identify the latest clinical trials across global registries.

login

or

view full example data

Identify the latest clinical trials across global registries.

Approval

Accelerate your research with the latest regulatory approval information.

login

or

view full example data

Accelerate your research with the latest regulatory approval information.

Biosimilar

Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

login

or

view full example data