Lyophilized Monoclonal Antibody Formulation for TTR Stabilization

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Solution Overview

Problem

Current treatments for transthyretin-mediated amyloidosis lack effective solutions for stabilizing native TTR tetramers and preventing misfolding and aggregation, leading to tissue damage and organ dysfunction.

Innovation Solution

Pharmaceutical formulations comprising a monoclonal antibody with specific heavy and light chain variable regions, combined with buffers, sugars, and surfactants, are developed to stabilize TTR and prevent aggregation, including a lyophilized form for reconstitution and administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for transthyretin-mediated amyloidosis, then current therapeutic options are limited, but the ability to stabilize native TTR tetramers and prevent misfolding and aggregation is insufficient

Engineering Contradiction:

Improveability to stabilize TTR and prevent aggregationVSAvoideffectiveness for different disease forms

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops formulations with optimized parameters including pH (5.0-6.5), buffer concentration (20 mM), sugar concentration (205-260 mM), and surfactant concentration (0.01-1% w/w) to stabilize TTR tetramers and prevent aggregation across different disease forms

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite pharmaceutical formulation combining monoclonal antibody (25-75 mg/mL), buffer (citrate, histidine, phosphate or succinate), sugar (sucrose or trehalose), and surfactant (polysorbate 20, 80 or poloxamer 188) to achieve synergistic stabilization of TTR and prevention of aggregation

Inventive Principle:

Principle #40Composite materials

2Reliability

If high concentration of antibody is used to improve therapeutic effect, then treatment efficacy increases, but formulation stability and solubility become more difficult to maintain

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidformulation stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent optimizes formulation parameters including pH (5.0-6.5), ionic strength, and excipient concentrations to maintain antibody stability and solubility at therapeutic concentrations (25-75 mg/mL), preventing aggregation while maintaining efficacy

Inventive Principle:

Principle #35Parameter changes

3Duration of action of stationary object

If lyophilized formulation is developed for improved storage and handling, then stability during storage increases, but reconstitution process and potential for aggregation are introduced

Engineering Contradiction:

Improvestorage stabilityVSAvoidaggregation during reconstitution

Core Design Contradiction:

Duration of action of stationary objectVSObject-affected harmful factors

Solution Approach 1:

The patent incorporates stabilizing excipients (sugar at 205-260 mM, surfactant at 0.01-1% w/w, and buffer at 20 mM) into the lyophilized formulation before storage, so that upon reconstitution, these pre-positioned components immediately prevent aggregation and maintain antibody stability

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The formulation uses sugar (sucrose or trehalose) and surfactant as intermediary substances that mediate between the antibody and the reconstitution environment, preventing direct aggregation pathways while the antibody re dissolves

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The formulations effectively stabilize TTR, reduce aggregation, and provide a stable and effective treatment for transthyretin-mediated amyloidosis, offering a prophylactic and therapeutic option for patients with or at risk of the disease.

Implementation Method 1

a sugar present at a concentration within the range from about 205 mM to about 260 mM, wherein the sugar is sucrose or trehalose

Methodology Applied

Scientific EffectPreferential exclusion:

Implementation Method 2

a buffer present at a concentration of about 20 mM, wherein the buffer is citrate, histidine, phosphate or succinate; wherein the formulation is characterized by a pH within the range from about 5.0 to about 6.5

Methodology Applied

Scientific EffectBuffering:

Implementation Method 3

a surfactant present at a concentration within the range from about 0.01% to about 1% by weight; wherein the surfactant is polysorbate 20, polysorbate 80 or poloxamer 188

Methodology Applied

Scientific EffectSurfactant action: Surfactant

Implementation Method 4

The invention provides pharmaceutical formulations that comprise... wherein the formulation is characterized by a pH within the range from about 5.0 to about 6.5

Methodology Applied

Scientific EffectLyophilization: Freeze Drying

Data Source

PatentUS11873332B2Lyophilized formulation of a monoclonal antibody against transthyretin

Publication Date: 2024.01.16 PROTHENA BIOSCIENCES INC

AI summary

The invention provides antibody formulations and methods useful for prophylaxis or treatment of transthyretin-related amyloidosis.