Chimpanzee Adenovirus Vector Seroprevalence Reduction

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Solution Overview

Problem

Current adenovirus vectors face challenges in delivering molecules effectively due to pre-existing immunity in humans, particularly humoral immunity against adenoviral proteins like fiber, penton, and hexon, which limits their productivity and immunogenicity.

Innovation Solution

The development of isolated polynucleotides and polypeptides from chimp adenovirus ChAd155, specifically the fiber, penton, and hexon proteins, which are used to create recombinant adenoviruses with reduced seroprevalence, enhancing productivity and immunogenicity by minimizing affinity to pre-existing neutralizing antibodies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If human adenovirus vectors are used for gene transfer, then efficient gene delivery is achieved, but pre-existing humoral immunity against adenoviral proteins (fiber, penton, hexon) limits productivity and immunogenicity

Engineering Contradiction:

Improvegene delivery efficiencyVSAvoidimmunogenicity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies inversion by switching from human adenovirus vectors to chimpanzee adenovirus vectors. Since chimpanzees are not the natural host for human adenoviruses, the human population lacks pre-existing immunity against ChAd vectors, thereby reversing the immunity problem that plagues human adenovirus-based vaccines and gene therapies

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the viral species parameter from human adenovirus to chimpanzee adenovirus. This parameter change fundamentally alters the immune recognition profile, allowing the vector to evade pre-existing neutralizing antibodies while maintaining efficient gene delivery capabilities

Inventive Principle:

Principle #35Parameter changes

2Reliability

If chimpanzee adenovirus vectors are used to overcome pre-existing immunity, then reduced seroprevalence is achieved, but serologic cross reactivity between human and chimp adenoviruses is possible

Engineering Contradiction:

Improvereduced seroprevalenceVSAvoidserologic cross reactivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by selectively modifying specific capsid proteins (fiber, penton, hexon) of the chimpanzee adenovirus vector. These localized modifications reduce serologic cross-reactivity with human adenoviruses while preserving the essential function of efficient gene delivery to target cells

Inventive Principle:

Principle #3Local quality

3Ease of manufacture

If E1 genes are deleted and replaced with transgene cassette, then replication defective recombinant virus is created for safety, but transgene expression and immunogenicity are limited by host immunity

Engineering Contradiction:

Improvesafety of recombinant virusVSAvoidtransgene expression

Core Design Contradiction:

Ease of manufactureVSProductivity

Solution Approach 1:

The patent uses chimpanzee adenovirus as an intermediary system. The ChAd vector serves as a mediator that delivers transgenes to human cells without being recognized by pre-existing human anti-adenovirus immunity, thereby enabling both safe replication-defective design and high transgene expression

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11254710B2Adenovirus polynucleotides and polypeptides

Publication Date: 2022.02.22 GLAXOSMITHKLINE BIOLOGICALS SA

AI summary

There is provided inter alia an isolated polynucleotide, wherein the polynucleotide encodes a polypeptide selected from the group consisting of:(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and(c) a polypeptide having the amino acid sequence according to SEQ ID NO: 3.