Invention Title:

RECEPTOR ELIMINATION BY UBIQUITIN LIGASE RECRUITMENT

Publication number:

US20240239891

Publication date:
Section:

Chemistry; metallurgy

Class:

C07K16/2818

Inventors:

Assignee:

Applicant:

Drawings (4 of 41)

Smart overview of the Invention

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR) constructs are designed to facilitate the targeted elimination of specific proteins associated with various diseases, particularly cancer. These constructs consist of two variable domain heavy chain antibodies (VHHs): one that binds to an E3 Ubiquitin Ligase and another that targets a specific protein. The unique feature of these constructs is the ability to simultaneously engage with both the E3 Ubiquitin Ligase and the target protein, which may lead to the degradation or modulation of the target protein’s function.

Function of Ubiquitin in Cellular Processes

Ubiquitin (Ub) is a small protein that plays a crucial role in regulating protein degradation and various cellular processes through post-translational modification. The process of ubiquitylation involves a cascade of enzymatic reactions mediated by three classes of enzymes: E1 (activating enzymes), E2 (conjugating enzymes), and E3 (ligases). E3 ligases are particularly important as they provide substrate specificity, allowing for precise control over which proteins are tagged for degradation or functional alteration.

Composition and Variability of REULR Constructs

The REULR constructs can be defined by specific formulas that indicate the components involved, including VHHs for both target proteins and E3 Ubiquitin Ligases, linker molecules, and additional variability in their structure. These constructs can include multiple VHHs targeting either the E3 ligase or the target protein, enhancing their effectiveness. The choice of E3 ligase is critical, with particular emphasis on RING type ligases such as GRAIL and GODZILLA, which are implicated in various pathologies.

Applications in Disease Treatment

These constructs have significant potential in treating diseases characterized by abnormal protein expression, such as cancers and autoimmune disorders. By modulating the expression or degradation of specific proteins, REULR constructs can help restore normal cellular functions. The methods described involve administering pharmaceutical compositions containing these constructs to subjects, aiming for therapeutic effects through targeted protein modulation.

Kits and Methods for Implementation

Kits comprising REULR constructs along with pharmaceutical compositions or vectors are also proposed for practical applications in research and clinical settings. Methods for utilizing these constructs include contacting cells expressing target proteins with REULR constructs to achieve desired modulation outcomes. This innovative approach leverages the specificity of ubiquitin ligases to create targeted therapies that could revolutionize treatment strategies for various diseases.