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

DV02-02 — Antigen Ordering Map

HELIX-VAX-01 / HELIX-VAX-02

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

1. Purpose

The Antigen Ordering Map defines the sequence logic for arranging validated antigens inside the vaccine construct.

Correct ordering matters because antigen position can influence:

peptide processing efficiency
immune dominance
HLA presentation balance
CD8/CD4 response quality
immune escape resistance
CNS safety

2. SCF Antigen Ordering Principle

Highest-confidence, tumor-specific, clonal antigens are placed first.

Lower-confidence, broader-support, or backup antigens are placed later.

Clonal Neoantigen
↓
Confirmed Presented Neoantigen
↓
Fusion Antigen
↓
Secondary Neoantigen
↓
Tumor-Associated Antigen
↓
Backup / Exploratory Antigen

3. HELIX-VAX-01 Ordering Map

Multi-Antigen mRNA Lead Construct

Position	Antigen Class	Example ID	Placement Rationale
1	Clonal neoantigen	VAMI-001	Highest tumor specificity and primary immune target
2	Confirmed presented neoantigen	VAMI-002	Strong HLA presentation and high expression
3	Fusion antigen	VAMI-003	Tumor-specific junction target; high immunogenic value
4	Secondary neoantigen	VAMI-004	Supports breadth and escape resistance
5	Tumor-associated antigen	VAMI-005	Adds redundancy and broader tumor coverage
6	Alternative splice antigen	VAMI-006	Targets tumor-adaptive transcript behavior
7	Backup neoantigen	Backup-01	Supports antigen-loss mitigation
8	Backup TAA	Backup-02	Adds fallback coverage

4. HELIX-VAX-02 Ordering Map

Synthetic Long Peptide Backup Construct

Peptide Slot	Antigen Class	Example ID	Development Role
SLP-1	Clonal neoantigen	VAMI-001	Primary target
SLP-2	Confirmed neoantigen	VAMI-002	Secondary target
SLP-3	Fusion antigen	VAMI-003	Junction-specific target
SLP-4	Secondary neoantigen	VAMI-004	Backup tumor-specific target
SLP-5	Tumor-associated antigen	VAMI-005	Breadth support
SLP-6	Alternative splice antigen	VAMI-006	Exploratory backup

5. Ordering Rules

Rule	Action
Avoid antigen crowding	Do not place highly similar peptides next to each other
Preserve neoantigen dominance	Keep TAAs after neoantigens and fusion antigens
Maintain HLA diversity	Alternate HLA-A, HLA-B, HLA-C dominant peptides when possible
Reduce immune escape	Include clonal and backup targets
Protect CNS safety	Do not include yellow-risk antigens in early dominant positions
Exclude red-risk antigens	Remove from construct entirely

6. Immunodominance Control

The construct should avoid allowing one antigen to dominate the immune response excessively.

Risk	Mitigation
One antigen dominates T-cell response	Balance antigen class and HLA coverage
TAA suppresses neoantigen priority	Place TAA later
Low-confidence antigen distracts immune system	Use only in backup or exploratory construct
CNS-risk antigen becomes dominant	Exclude or place only after additional safety review

7. SCF Ordering Score

Ordering Priority Score =
Clonality
+ Tumor Specificity
+ Presentation Confidence
+ HLA Diversity
+ Escape Resistance
- CNS Risk
- Immunodominance Risk

Score Range	Placement
≥85	Early construct position
70–84	Middle construct position
55–69	Late / backup position
<55	Exclude or redesign

8. Final Ordering Recommendation

HELIX-VAX-01 Lead Construct

5' Cap
↓
UTR Optimization Region
↓
VAMI-001 — Clonal Neoantigen
↓
Processing Linker
↓
VAMI-002 — Confirmed Presented Neoantigen
↓
Processing Linker
↓
VAMI-003 — Fusion Antigen
↓
Processing Linker
↓
VAMI-004 — Secondary Neoantigen
↓
Processing Linker
↓
VAMI-005 — Tumor-Associated Antigen
↓
Processing Linker
↓
VAMI-006 — Alternative Splice Antigen
↓
Processing Linker
↓
Backup-01 — Escape-Resistance Neoantigen
↓
Processing Linker
↓
Backup-02 — Backup Tumor-Associated Antigen
↓
Poly(A) Tail

Status

DV02-02 Antigen Ordering Map: Complete

Next Sub-Deliverable: DV02-03 Linker Architecture Plan