Designed Ankyrin Repeat Domains With Altered Capping Residues

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Solution Overview

Problem

Designed ankyrin repeat domains exhibit fast clearance and short terminal half-life despite being genetically fused to a domain with binding specificity for serum albumin, necessitating improved pharmacokinetic properties.

Innovation Solution

Altering certain amino acid residues in the N-terminal and/or C-terminal capping modules of the designed ankyrin repeat domain, particularly at specific positions, to enhance pharmacokinetic properties and prolong terminal half-life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of stationary object

If a designed ankyrin repeat domain is genetically fused to a domain with binding specificity for serum albumin, then the terminal half-life is expected to be prolonged, but the observed terminal half-life remains short due to fast clearance

Engineering Contradiction:

Improveterminal half-lifeVSAvoidpharmacokinetic property

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent applies local quality by specifically modifying the N-terminal and C-terminal capping modules of the ankyrin repeat domain rather than the entire protein structure. These terminal regions are locally altered to contain negatively charged residues (aspartic acid or glutamic acid) that interact with the basic residues of serum albumin, creating localized binding sites that extend the protein's circulation half-life without affecting the overall structure or function of the ankyrin repeat domain.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the amino acid composition at specific positions (positions 2 and 3 of the N-terminal capping module, and positions 2 and 3 of the C-terminal capping module) to introduce negatively charged residues. This changes the electrostatic parameters of the protein surface, enabling favorable electrostatic interactions with serum albumin and thereby improving pharmacokinetic properties including terminal half-life.

Inventive Principle:

Principle #35Parameter changes

2Duration of action of stationary object

If amino acid residues in capping modules are altered to improve pharmacokinetic properties, then terminal half-life is prolonged, but the amino acid sequence complexity increases

Engineering Contradiction:

Improveterminal half-lifeVSAvoidamino acid sequence

Core Design Contradiction:

Duration of action of stationary objectVSDevice complexity

Solution Approach 1:

The complexity increase is minimized by applying local quality - only specific positions in the capping modules (positions 2 and 3 of both N-terminal and C-terminal capping modules) are modified to contain negatively charged residues. The rest of the amino acid sequence remains unchanged, maintaining simplicity while achieving the desired pharmacokinetic improvement through localized sequence optimization.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12435445B2Designed ankyrin repeat domains with altered surface residues

Publication Date: 2025.10.07 MOLECULAR PARTNERS AG

AI summary

The present invention relates to designed ankyrin repeat domains with altered surface residues, as well as to proteins comprising such a designed ankyrin repeat domain, nucleic acids encoding such domains or proteins, methods of preparing such proteins, pharmaceutical compositions comprising such proteins or nucleic acids, and the use of such proteins, nucleic acids or pharmaceutical compositions in the treatment of diseases.