Engineered Outer Domain Immunogens for HIV bnAb Precursor Binding
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Solution Overview
Problem
Current HIV vaccine development faces challenges in eliciting broadly neutralizing antibodies (bnAbs) due to poor binding of Env to unmutated precursors, particularly for VRC01-class bnAbs, which lack detectable affinity for native HIV Envelope glycoproteins and have rare light chain complementarity determining region 3 (CDRL3) characteristics.
Innovation Solution
Engineered outer domain (eOD) immunogens, such as eOD-GT8 and eOD-GT10, are designed to bind to VRC01-class bnAb precursors, promoting affinity maturation and inducing mutations that enable binding to near-native HIV-1 gp120 constructs, using deep mutational scanning and multi-target optimization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native HIV Env glycoprotein is used as immunogen, then it maintains natural structure and antigenicity, but it fails to bind to unmutated precursors of broadly neutralizing antibodies
Solution Approach 1:
The patent segments the HIV Env glycoprotein into its outer domain (OD) component, which is then engineered with specific mutations. This segmentation allows the OD to be optimized for binding to bnAb precursors while maintaining the ability to present relevant epitopes, resolving the contradiction between binding affinity and structural fidelity.
Solution Approach 2:
The patent applies parameter changes by introducing specific mutations in the outer domain of gp120, particularly in regions that interact with bnAb precursors. These mutations enhance binding affinity to unmutated precursors while preserving the overall structural framework and key epitopic features of the native Env protein.
2Manufacturing precision
If engineered mutations are introduced to improve binding to bnAb precursors, then affinity maturation is promoted, but the structure deviates from native HIV Env
Solution Approach 1:
The patent applies local quality by introducing mutations specifically in the outer domain region of gp120 that is most relevant for bnAb precursor binding, while leaving other critical regions of the protein unchanged. This localized engineering approach improves binding specificity without compromising overall structural integrity.
Solution Approach 2:
The patent employs preliminary action by pre-engineering the outer domain with mutations that anticipate and facilitate subsequent affinity maturation processes. These pre-introduced mutations create a scaffold that guides the affinity maturation pathway toward generating bnAbs with desired specificities.
3Productivity
If conventional immunogens are used, then production is straightforward, but they fail to elicit broadly neutralizing antibodies due to poor precursor binding
Solution Approach 1:
The patent uses preliminary action by performing deep mutational scanning and computational design before final immunogen production. This preliminary engineering phase identifies optimal mutations that enhance precursor binding, enabling subsequent efficient production of highly effective immunogens through established molecular biology techniques.
Solution Approach 2:
The patent introduces an intermediary design phase involving deep mutational scanning and computational modeling between the selection of native Env and the production of immunogens. This intermediary step identifies optimal mutations without requiring complex manufacturing processes, bridging the gap between simple production and high efficacy.
Data Source
AI summary
The present invention relates to engineered outer domain (eOD) immunogens of HIV gp120 and mutants thereof and methods of making and using the same. The present invention also includes fusions of eOD to various protein multimers to enhance immunogenicity. The mutant eODs bind to neutralizing antibody precursors. The mutant eODs can activate germline precursors on the pathway to eliciting a broadly neutralizing antibody (bnAb) response. The invention also relates to immunized knock-in mice expressing germline-reverted heavy chains. Induced antibodies showed characteristics of bnAbs and mutations that favored binding to near-native HIV-1 gp120 constructs. In contrast, native-like immunogens failed to activate precursors. The invention also relates to rational epitope design that can prime rare B cell precursors for affinity maturation to desired targets.