PROJECT HELIX-HTT | Huntington’s-Adjacent Neuro-Oncology Vaccine Program | SCF HLA Compatibility Matrix (HCM)

D-WS3-001C

SCF HLA Compatibility Matrix (HCM)

PROJECT HELIX-HTT | Huntington’s-Adjacent Neuro-Oncology Vaccine Program

DOCUMENT CONTROL HEADER

Program Code: SCF-ARGEN-HTT-NO-01

Workflow Stage: Discovery Phase

Deliverable: Core Deliverable #4

Document Code: SCF-HCM-NO-0001

Purpose: Define patient-specific antigen presentation capability and prioritize vaccine antigens based on HLA compatibility, presentation probability, and immune activation potential.

1. PURPOSE OF THE HLA COMPATIBILITY MATRIX

The HLA Compatibility Matrix determines:

Which peptides can be presented by the patient’s immune system
Which neoantigens are most likely to activate T-cells
Which candidate vaccine antigens have the highest probability of generating durable anti-tumor immunity

The HCM serves as the bridge between:

Mutation Catalog
        +
Expression Atlas
        ↓
HLA Compatibility Matrix
        ↓
Presented Antigen Library

2. SCIENTIFIC OVERVIEW

What Is HLA?

Human Leukocyte Antigen (HLA) molecules are cellular proteins that display peptide fragments on the cell surface.

These molecules act as:

Biological Display Cases

Cell Interior
     ↓
Protein Fragment
     ↓
HLA Molecule
     ↓
T Cell Inspection

If a peptide appears foreign, immune cells may attack.

Why HLA Matters for Vaccines

A peptide cannot function as a vaccine antigen unless:

✓ Generated by tumor

✓ Expressed by tumor

✓ Processed into peptide

✓ Presented by HLA

✓ Recognized by T-cells

3. HLA SYSTEM ARCHITECTURE

Class I HLA

Primary role:

Activate CD8 Cytotoxic T Cells

Molecules

Locus

HLA-A

HLA-B

HLA-C

Class II HLA

Primary role:

Activate CD4 Helper T Cells

Molecules

Locus

HLA-DR

HLA-DQ

HLA-DP

4. MASTER HLA PROFILE

HCM TABLE 1

HLA Class	Allele	Resolution	Confidence
HLA-A	Example	4-digit	High
HLA-B	Example	4-digit	High
HLA-C	Example	4-digit	High
HLA-DRB1	Example	4-digit	High
HLA-DQB1	Example	4-digit	High

5. ANTIGEN-HLA COMPATIBILITY TABLE

HCM TABLE 2

Antigen ID	Peptide	HLA Allele	Predicted Binding	Rank
ANT-001	Example	HLA-A	Strong	A
ANT-002	Example	HLA-B	Moderate	B
ANT-003	Example	HLA-C	Weak	C

6. PRESENTATION SCORING SYSTEM

HLA Presentation Score (HPS)

Calculated from:

Variable	Description
Binding Affinity	Peptide-HLA strength
Stability	Duration of presentation
Processing Probability	Likelihood of generation
Expression Support	Transcript abundance
Immunopeptidomics Support	Direct presentation evidence

Formula

HPS =
Binding Affinity
+
Complex Stability
+
Processing Probability
+
Expression Support
+
Presentation Evidence

7. CLASS I PRIORITIZATION MODULE

Objective

Identify antigens most likely to activate:

CD8 Cytotoxic T Cells

Desired characteristics:

✓ Strong HLA-A binding

✓ Strong HLA-B binding

✓ Stable presentation

✓ Tumor specificity

Priority Classes

Class	Meaning
HLA-I-A	Strong candidate
HLA-I-B	Backup candidate
HLA-I-C	Exploratory

8. CLASS II PRIORITIZATION MODULE

Objective

Identify antigens most likely to activate:

CD4 Helper T Cells

Desired characteristics:

✓ Broad helper response

✓ Cytokine support

✓ Long-term immune memory

Priority Classes

Class	Meaning
HLA-II-A	Strong candidate
HLA-II-B	Backup candidate
HLA-II-C	Exploratory

9. POPULATION COVERAGE ANALYSIS

Objective

Estimate broader applicability.

Metrics

Metric	Description
HLA Coverage	Population compatibility
Allele Frequency	Prevalence
Vaccine Scalability	Development potential

SCF Vaccine Strategy

Vaccine Type	HLA Requirement
Personalized Vaccine	Patient-specific
Semi-Personalized	Cohort-specific
Off-the-Shelf	Population-wide

10. IMMUNE ACTIVATION POTENTIAL

Cytotoxic Potential Score (CPS)

Measures:

Predicted CD8 activation
Tumor-killing potential

Helper Potential Score (HLS)

Measures:

CD4 activation
Immune amplification

Composite Immune Activation Score (CIAS)

CIAS =
CPS
+
HLS

11. CNS SAFETY FILTERS

Mandatory Exclusions

Reject peptides with:

✗ High similarity to neuronal proteins

✗ Essential CNS protein overlap

✗ Autoimmune neurotoxicity risk

✗ High normal-brain expression

Safety Classification

Class	Meaning
Green	Acceptable
Yellow	Review
Red	Exclude

12. SCF HLA COMPATIBILITY SCORE

Final HCM Score

HCM Score =
HPS
+
CIAS
+
Tumor Specificity

-
CNS Risk

-
Immune Escape Risk

13. HCM OUTPUT FILES

HCM-01

Complete HLA Profile

HCM-02

Peptide-HLA Binding Matrix

HCM-03

Class I Priority Table

HCM-04

Class II Priority Table

HCM-05

Population Coverage Analysis

HCM-06

SCF HLA Compatibility Score Table

14. INTEGRATION WITH OTHER DELIVERABLES

Deliverable	Relationship
Mutation Catalog	Source mutations
Expression Atlas	Expression validation
HLA Compatibility Matrix	Presentation prediction
Presented Antigen Library	Experimental confirmation

15. DECISION GATE

Advance to Presented Antigen Library generation if:

✓ HLA typing complete

✓ Binding prediction complete

✓ Compatibility scoring complete

✓ CNS safety review complete

✓ Top-ranked presentation candidates identified

DELIVERABLE SUMMARY

The HLA Compatibility Matrix provides:

Patient-specific antigen presentation mapping
Vaccine compatibility assessment
Immune activation prioritization
Safety filtering
Foundation for immunopeptidomics validation

STATUS

Core Deliverable #4: COMPLETE

NEXT DELIVERABLE: Core Deliverable #5 — Presented Antigen Library (PAL)

Reply NEXT to generate Deliverable #5.