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

SCF Therapeutic Vaccine Development Pipeline

DOCUMENT CONTROL HEADER

Program: PROJECT HELIX-HTT

Platform: SCF Therapeutic Vaccine Platform

Phase: Phase II — Preclinical Development

Program Code: SCF-VAX-PRECLINICAL-HTT-01

Development Stage: Post-Discovery / Pre-IND

Primary Output: IND-Enabling Therapeutic Vaccine Candidate

EXECUTIVE SUMMARY

Phase I successfully established:

✓ Multi-Omics Dataset

✓ Mutation Catalog

✓ Expression Atlas

✓ HLA Compatibility Matrix

✓ Presented Antigen Library

✓ SCF Microenvironment Report

✓ Ranked Antigen Candidate Library

✓ Vaccine Candidate Package

Phase II transitions from biological discovery into functional vaccine development.

The central question changes from:

“What should we target?”

to

“Can we safely generate durable anti-tumor immunity against these targets?”

PHASE II MASTER WORKFLOW

MODULE 1

ANTIGEN VALIDATION PROGRAM

Purpose

Confirm all selected vaccine antigens are:

• Expressed
• Presented
• Immunogenic
• Stable

Workstreams

M1-A

Antigen Expression Validation

Methods:

• qPCR
• RNA-seq
• ddPCR

Endpoints:

• Expression abundance
• Expression stability

M1-B

Antigen Presentation Validation

Methods:

• Immunopeptidomics
• HLA pull-down
• Flow cytometry

Endpoints:

• Surface presentation
• HLA occupancy

M1-C

Antigen Persistence Studies

Determine:

• Temporal stability
• Evolutionary stability
• Escape susceptibility

Deliverable

DV-01

Validated Antigen Master Inventory

MODULE 2

VACCINE CONSTRUCT ENGINEERING

Objective

Design the vaccine itself.

Platform A

Synthetic Long Peptide (SLP)

Advantages:

• Manufacturing simplicity
• Multi-HLA compatibility
• Regulatory familiarity

Platform B

mRNA Vaccine

Advantages:

• Rapid redesign
• Personalized deployment
• Multi-antigen encoding

Platform C

Dendritic Cell Vaccine

Advantages:

• Strong antigen presentation
• Highly personalized

SCF Recommendation

Primary Development Path:

Multi-Antigen mRNA Platform

Backup:

Synthetic Long Peptide Platform

Deliverable

DV-02

Vaccine Construct Engineering Package

MODULE 3

ADJUVANT OPTIMIZATION PROGRAM

Purpose

Maximize immune activation.

Candidate Categories

A

TLR Agonists

B

STING Agonists

C

Dendritic Cell Activators

D

Cytokine-Support Systems

Optimization Criteria

• CD8 activation
• Memory formation
• CNS compatibility
• Low neuroinflammation

Deliverable

DV-03

Adjuvant Selection Package

MODULE 4

DENDRITIC CELL ACTIVATION PROGRAM

Objective

Determine antigen presentation efficiency.

Assays

DC Maturation

Markers:

• CD80
• CD86
• CD40

Antigen Uptake

Measure:

• Processing
• Presentation

Cytokine Profiling

Markers:

• IL-12
• IFNα
• IFNβ

Deliverable

DV-04

DC Activation Report

MODULE 5

T-CELL ACTIVATION PROGRAM

Objective

Determine whether vaccine candidates generate functional immunity.

Assays

ELISPOT

Endpoints:

• IFNγ
• TNFα

Intracellular Cytokine Staining

Endpoints:

• CD8 activation
• CD4 activation

Tetramer Assays

Endpoints:

• Antigen-specific T-cells

Deliverable

DV-05

Immune Activation Report

MODULE 6

TUMOR KILLING MODELS

Objective

Determine whether activated T-cells kill target tumor cells.

Model Systems

2D Models

Tumor Cell Lines

3D Models

Tumor Organoids

Co-Culture Systems

Tumor + Immune Cells

Endpoints

• Cell death
• Cytotoxicity
• Tumor burden reduction

Deliverable

DV-06

Tumor Killing Assessment

MODULE 7

NEUROIMMUNE SAFETY PROGRAM

Highest Priority Module

Purpose

Prevent:

• Autoimmune encephalitis
• Neurotoxicity
• Excessive microglial activation

Safety Domains

Neuronal Cross-Reactivity

Microglial Activation

Cytokine Storm Risk

Neuroinflammation

Deliverable

DV-07

Neuroimmune Safety Report

MODULE 8

PK / PD & BIODISTRIBUTION PROGRAM

Objectives

Characterize:

• Distribution
• Persistence
• Exposure

Endpoints

PK

• Exposure profile
• Clearance

PD

• Immune activation
• Antigen-specific responses

Biodistribution

Evaluate:

• CNS exposure
• Lymphatic trafficking
• Tissue distribution

Deliverable

DV-08

PK/PD & Biodistribution Package

MODULE 9

GLP TOXICOLOGY PROGRAM

Objectives

Establish safety margins.

Required Studies

Acute Toxicity

Repeat-Dose Toxicity

Local Tolerance

Immunotoxicity

Neurotoxicity

Deliverable

DV-09

GLP Toxicology Package

MODULE 10

IND-ENABLING VACCINE PACKAGE

Purpose

Prepare regulatory submission package.

Components

Pharmacology

• MoA
• MeA

Safety

• Toxicology

Manufacturing

• CMC

Clinical Entry

• FIH rationale

Deliverable

DV-10

IND-Enabling Vaccine Development Package

SCF SUCCESS METRICS

Vaccine Potency Index (VPI)

Measures:

• Antigen breadth
• T-cell activation
• Presentation quality

Immune Durability Index (IDI)

Measures:

• Memory formation
• Response persistence

CNS Compatibility Index (CCI)

Measures:

• Neuroimmune safety
• CNS tolerance

Composite Vaccine Development Score

CVDS =
Potency
+
Durability
+
Safety
+
Microenvironment Compatibility

PHASE II GO/NO-GO GATES

Advance to IND-Enabling Development If:

✓ Robust CD8 response

✓ Durable immune memory

✓ Demonstrated tumor killing

✓ Acceptable CNS safety

✓ Favorable PK/PD

✓ Acceptable GLP toxicology

STRATEGIC RESEARCH PATHWAYS

1. Personalized Neoantigen Vaccine Platform

Individualized vaccines derived from patient-specific antigen libraries.

2. SCF Neuroimmune Conditioning Systems

Microenvironment optimization to improve vaccine responsiveness.

3. HTT-Adjacent Stress Antigen Research Program

Experimental exploration of repair-stress, hypoxia-adaptation, and neuroimmune-remodeling antigens.

STRATEGIC DEVELOPMENT PATHWAYS

1. Multi-Antigen mRNA Therapeutic Vaccine

Primary development candidate.

2. Synthetic Long Peptide Backup Platform

Manufacturing-risk mitigation pathway.

3. Combination Immunotherapy Platform

Vaccine + microenvironment conditioning + immune checkpoint modulation.

STATUS

PHASE II — PRECLINICAL VACCINE DEVELOPMENT PROGRAM: INITIATED

Next Recommended Deliverable

Module 1 (DV-01): Validated Antigen Master Inventory

This becomes the first executable package and serves as the foundation for all downstream vaccine construct engineering activities.