PBD Antibody-Drug Conjugate Composition for Stability-Solubility Balance

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Solution Overview

Problem

Existing pyrrolobenzodiazepine-based antibody drug conjugates (ADCs) face challenges in maintaining stability while ensuring adequate solubility for efficient manufacturing and therapeutic efficacy.

Innovation Solution

Development of pharmaceutical compositions comprising antibody-drug conjugates with specific PBD drug-linkers, including a cleavable linker, spacer, and self-immolative moiety, stabilized by a pH of at least 6.2, buffering agents like histidine, surfactants such as polysorbate 20, and sugars like sucrose, to enhance stability and solubility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If the pH is increased to at least 6.2, then the stability of PBD payloads is improved, but the solubility may be compromised

Engineering Contradiction:

Improvestability of PBD payloadsVSAvoidsolubility of PBD payloads

Core Design Contradiction:

Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

The patent applies parameter changes by optimizing the pH to at least 6.2, which resolves the contradiction between stability and solubility. This specific pH parameter improvement prevents degradation of PBD payloads while maintaining adequate solubility for manufacturing and therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If buffering agents like histidine are added, then the stability of the formulation is improved, but the complexity of the composition increases

Engineering Contradiction:

Improveformulation stabilityVSAvoidcomplexity of composition

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent uses buffering agents like histidine as intermediaries to maintain formulation stability. These agents mediate between the PBD payloads and the aqueous environment, preventing degradation while contributing to overall formulation integrity. The surfactant polysorbate 20 similarly acts as an intermediary to maintain solubility and prevent aggregation.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If surfactants such as polysorbate 20 are included, then the solubility of PBD payloads is improved, but the manufacturing complexity increases

Engineering Contradiction:

Improvesolubility of PBD payloadsVSAvoidmanufacturing efficiency

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by incorporating surfactants like polysorbate 20 at optimized concentrations. This improves the solubility of PBD payloads, enabling efficient manufacturing processes. The surfactant reduces surface tension and prevents aggregation, facilitating homogeneous formulation preparation.

Inventive Principle:

Principle #35Parameter changes

4Stability of the object's composition

If sugars like sucrose are added, then the stability during storage is improved, but the osmolarity and complexity of the formulation increase

Engineering Contradiction:

Improvestorage stabilityVSAvoidformulation complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent uses sugars like sucrose as protective agents that provide beforehand cushioning during storage. These excipients prevent degradation, aggregation, and precipitation of PBD payloads during storage and handling. The sugar molecules form a protective matrix around the active ingredients, maintaining stability without requiring additional stabilization mechanisms.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

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 maintain the stability and solubility of PBD payloads, ensuring effective manufacturing and therapeutic efficacy, particularly in treating proliferative disorders like cancer.

Implementation Method 1

the pharmaceutical composition has a pH of at least about 6.2... The pharmaceutical composition may comprise a buffering agent, such as histidine/histidine HCl

Methodology Applied

Scientific EffectpH buffering:

Implementation Method 2

The pharmaceutical composition may comprise a surfactant, such as polysorbate 20... the concentration of the surfactant, such as polysorbate 20, is from about 0.01 to 0.1% w/v

Methodology Applied

Scientific EffectSurfactant action: Surfactant

Implementation Method 3

The pharmaceutical composition may comprise a sugar, such as sucrose... the concentration of the sugar, such as sucrose, is from about 100 mM to about 250 mM

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentUS20250381282A1Composition comprising a pyrrolobenzodiazepine-based antibody drug conjugate

Publication Date: 2025.12.18 ADC THERAPEUTICS SA

AI summary

This disclosure relates to pharmaceutical formulations comprising pyrrolobenzodiazepine-based antibody-drug conjugates (AD-Cs) having a pH of 6.3 to 6.9. In one embodiment, the ADC is selected from ADCT-601 (mipastamab uzoptirine) and ADCT-701.