Glycotope, a clinical stage biotechnology company, and Tubulis, developing uniquely matched protein drug-conjugates,  have signed a research and feasibility agreement. Based on the agreement, Glycotope receives non-exclusive access to Tubulis’ proprietary Tub-tag® technology for one of its antibody-drug conjugate (ADC-) candidates.

Glycotope uses glyco-biology expertise to develop highly innovative antibody-based therapeutics in immuno-oncology and oncology. The company’s Glycobodies are designed to recognize protein targets with specific post-translational modifications that are only present on tumor cells and not on normal cells. These targeted specific glyco-epitopes are used to generate new, first-in-class, therapeutic antibodies.

The company’s lead candidate, gatipotuzumab (formerly PankoMab-GEX®), targets the tumor-specific carbohydrate-protein epitope TA-MUC1 (attached to the tandem repeat region of MUC1 present on tumor cells, but not on healthy cells) and is in clinic development for the treatment of patients with solid tumors in combination with an anti-EGRF antibody.[1] Gatipotuzumab demonstrated a good safety profile and anti-tumor activity in a single agent Phase I study. The compound is currently in a Phase II study as maintenance therapy for recurrent ovarian cancer.

Gatipotuzumab is also being developed in as the antibody-part of a novel, investigational ADC Glycotope is developing in collaboration with Daiichi Sankyo (using Daiichi Sankyo proprietary ADC technology) and as a bispecific IL-15 and CD-3.

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A schematic depiction of Tubulis’ Tub-tag technology. In step a: A tyrosine derivative carrying a unique chemical entity is ligated by the Tubulin Tyrosine Ligase to the Protein of Interest. Then, a subsequent bioorthogonal reaction is used for the site-specific attachment of a payload. In step b: The payload is attached to the Protein of Interest via a Tubulin Tyrosine Ligase catalyzed one-step ligation. Courtesy: The Ludwig-Maximilians-Universität München,  München, Germany (Reproduced with permission)

Tub-tag technology
Tubulis’ Tub-tag technology is a novel chemoenzymatic labeling method in which the developers repurposed the tubulin associated enzyme Tubulin Tyrosine Ligase (TTL) for the attachment of functional moieties at the C-terminus of any protein of interest. It fuses a short protein (α-tubulin) sequence to such protein of interest (POI).* In short, the TTL catalyzes the ligation of unnatural tyrosine derivatives to a target protein which subsequently serve as bioorthogonal handles for the site-specific coupling of cytotoxic payloads.[2]

Using these aspects of microtubule biology Tubulis’ Tub-tag technology introduces a highly beneficial microenvironment for site-specific and stable payload conjugation.  This approach broadens the spectrum of currently possible protein-drug combinations.

“We are pleased to enter this collaboration and working closely with Tubulis on identifying novel ADC candidates,” said Sven Bahrke, Senior Director at Glycotope.

“We believe that Tubulis’ ADC discovery and development technologies add unique and innovative aspects to the field of ADC conjugation,” Bahrke added.

P5 Screening Platform
In addition to receiving access to Tubulis’ Tub-tag technology, Glycotope receives the option to evaluate the potential of Tubulis’ ADC screening platform P5.

The P5 screening platform is an initial screening platform with fast conjugation to rapidly identify novel protein-drug combinations for therapeutic use. The platform is a cysteine-based conjugation method that shows an increased reaction selectivity and high chemical flexibility. It enables the fast and efficient conjugation of any antibody to any payload. The selected best combinations can then be advanced via the Tub-tag conjugation technology to create uniquely stable therapeutic candidates.

“This agreement with an experienced antibody developer in oncology enables us to further validate our advanced ADC technologies,” noted Dominik Schumacher, Tubulis’ Chief Executive Officer.

“We look forward to collaborate with the Glycotope team to create novel, uniquely stable therapeutic candidates,” he concluded.

The companies did not disclose financial terms of the collaboration.

Clinical trials
PankoMab-GEX™: Dose Escalation Study – NCT01222624
Combination of Gatipotuzumab and Tomuzotuximab in Patients With Solid Tumors (GATTO) – NCT03360734

[1] Fiedler W, DeDosso S, Cresta S, Weidmann J, Tessari A, Salzberg M, Dietrich B, et al. A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. Eur J Cancer. 2016 Aug;63:55-63. doi: 10.1016/j.ejca.2016.05.003. Epub 2016 Jun 7. [Pubmed][Article]
[2] Research Group Tubulis. Online. Last accessed Devember 10, 2019

*A subsequent bioorthogonal reaction is used for the site-specific attachment of a payload to the protein of interest via a tubulin tyrosine ligase (TTL) catalyzed in one-step ligation.

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