Re-ordered HPV18 E6E7 Polypeptide Fragments for Therapeutic Vaccines

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Solution Overview

Problem

Current therapeutic vaccines for human papillomavirus (HPV) types 16 and 18 are ineffective in treating established genital lesions and have limitations such as high manufacturing costs, adverse effects, and suboptimal immune responses due to the use of synthetic long peptides and nucleic acid vaccines that pose oncogenic risks.

Innovation Solution

Development of nucleic acid molecules encoding polypeptides that comprise re-ordered fragments of HPV16 and HPV18 E6 and E7 proteins, minimizing transforming activity and undesired epitopes, and incorporating a leader sequence for enhanced expression and immunogenicity, which can be used in therapeutic vaccines to induce immune responses without the need for reactogenic adjuvants.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If synthetic long peptides are used in therapeutic vaccines, then manufacturing is simplified, but immune response is suboptimal and costs are high

Engineering Contradiction:

Improvemanufacturing simplicityVSAvoidimmune response efficacy

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The E6 and E7 proteins are divided into multiple fragments that are re-ordered and combined in a specific sequence. This segmentation allows the vaccine to present multiple epitopes effectively while maintaining manageable manufacturing complexity and reducing costs compared to full-length proteins.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent embeds multiple E6 and E7 fragments within a single polypeptide structure, creating a nested arrangement where smaller epitopic units are contained within a larger fusion protein framework. This nesting maximizes immune stimulation while simplifying manufacturing compared to using multiple separate peptide components.

Inventive Principle:

Principle #7Nested doll (Nesting)

2Adaptability or versatility

If nucleic acid vaccines encoding full-length E6 and E7 are used, then comprehensive epitope coverage is achieved, but transforming activity and oncogenic risks increase

Engineering Contradiction:

Improveepitope coverageVSAvoidtransforming activity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

Specific fragments of the E6 and E7 proteins are extracted and re-ordered to create a polypeptide that contains all necessary T-cell epitopes while excluding or minimizing the transforming regions. This extraction approach maintains comprehensive epitope coverage without the harmful transforming activity of full-length proteins.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies different quality characteristics to different regions of the polypeptide: certain segments retain full immunogenicity with multiple epitopes, while other segments are modified or truncated to reduce transforming activity. This local differentiation allows simultaneous achievement of comprehensive epitope coverage and reduced oncogenic risk.

Inventive Principle:

Principle #3Local quality

3Reliability

If reactogenic adjuvants are added to enhance immune response, then immunogenicity is improved, but adverse effects increase

Engineering Contradiction:

ImproveimmunogenicityVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The re-ordered polypeptide structure itself provides built-in immunogenicity enhancement through its unique arrangement of multiple E6 and E7 fragments. The protein's intrinsic properties, rather than external adjuvants, drive the immune response, eliminating the need for reactogenic adjuvants and their associated adverse effects.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The vaccine utilizes a composite polypeptide structure combining multiple E6 and E7 fragments in a specific re-ordered arrangement. This composite design inherently provides both epitope presentation and immunogenicity enhancement, replacing the need for separate adjuvant components and their harmful effects.

Inventive Principle:

Principle #40Composite materials

4Productivity

If leader sequences are added for enhanced expression, then manufacturing efficiency is improved, but protein structure complexity increases

Engineering Contradiction:

Improveexpression efficiencyVSAvoidprotein structure

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

Leader sequences are added to the N- or C-terminus of the re-ordered polypeptide to facilitate proper folding, secretion, and expression. These preliminary structural elements prepare the protein for optimal manufacturing and delivery without significantly complicating the core re-ordered E6/E7 fragment structure.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS10287323B2Therapeutic HPV18 vaccines

Publication Date: 2019.05.14 JANSSEN VACCINES & PREVENTION BV

AI summary

Provided is designer nucleic acid constructs and polypeptides that can be used as therapeutic vaccines against HPV18 and/or HPV16.