Hill Coefficient Drug Combination Selection

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Solution Overview

Problem

Current methods for identifying effective drug combinations for cancer treatment are unpredictable and fail to translate in vitro synergy to in vivo results, as they do not accurately predict clinical outcomes.

Innovation Solution

The use of the Hill coefficient from in vitro dose-response tests to select drug combinations for cancer treatment, where combinations with a Hill coefficient greater than 0.8 are administered, ensuring effective in vivo performance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current in vitro screening methods are used to identify drug combinations, then maximal effects or IC50 are measured, but the combinations rarely display promising results in vivo

Engineering Contradiction:

Improvein vitro effect measurementVSAvoidin vivo result prediction

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent changes the measurement parameter from IC50 (total effect) to Hill coefficient (steepness of dose-response curve). This parameter transformation enables in vitro assays to predict in vivo outcomes by focusing on the shape characteristics of the dose-response relationship rather than absolute effect magnitudes.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces traditional biological assay readouts (cell viability, tumor growth inhibition) with a mathematical model (Hill equation fitting). This substitution transforms complex biological responses into quantifiable curve characteristics that can be reliably compared and predicted across different experimental systems.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Productivity

If drug combinations are selected based on maximal in vitro effects, then strong in vitro activity is achieved, but clinical translation fails

Engineering Contradiction:

Improvein vitro therapeutic effectVSAvoidclinical outcome prediction

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent shifts the selection criterion from maximal effect magnitude (IC50) to curve steepness (Hill coefficient). Combinations with Hill coefficients greater than 0.8 are identified as having synergistic interactions that translate to in vivo efficacy, regardless of their absolute IC50 values.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent establishes a feedback loop where in vitro Hill coefficient measurements directly inform in vivo treatment selection. The mathematical model provides quantitative feedback that correlates in vitro curve characteristics with in vivo therapeutic outcomes, enabling rational drug combination design.

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20230093147A1Methods and compositions relating to improved combination therapies

Publication Date: 2023.03.23 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

The technology described herein is directed to in vitro methods of identifying or selecting combinations of therapeutic agents that are effective in vivo. These methods provide improved methods of treatment, e.g., treatment of cancer. Further, provided herein are novel combinations of anti-cancer agents which are demonstrated to have surprising efficacy.