DV-08 — PK/PD, Biodistribution & Systems Pharmacology Report

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

HELIX-VAX-01 / HELIX-VAX-02 IND-Enabling Pharmacology Package

DOCUMENT CONTROL HEADER

Program: PROJECT HELIX-HTT

Phase: II — Preclinical Vaccine Development

Module: 8 — PK/PD, Biodistribution & Systems Pharmacology

Document Code: SCF-DV08-PKPDSP-NO-0001

Purpose: Characterize vaccine biodistribution, immune trafficking, pharmacodynamic activity, antigen persistence, CNS exposure risk, and whole-body immunologic communication dynamics required for IND-enabling development.

1. EXECUTIVE SUMMARY

Traditional PK studies follow:

Drug
 ↓
Blood
 ↓
Target Tissue
 ↓
Clearance

Therapeutic vaccines behave differently.

HELIX-VAX follows:

Vaccine
 ↓
Injection Site
 ↓
APC Uptake
 ↓
Lymphatic Transport
 ↓
Lymph Node Processing
 ↓
Immune Expansion
 ↓
Systemic Immune Distribution
 ↓
Tumor Recognition
 ↓
Tumor Elimination

DV-08 therefore evaluates both:

Classical Pharmacology

• biodistribution
• persistence
• exposure
• clearance

and

SCF Systems Pharmacology

• APC trafficking
• immune communication
• whole-body response architecture
• neuroimmune exposure
• tumor-directed immune routing

2. SCF WHOLE-BODY IMMUNOLOGIC COMMUNICATION MAP

Primary Communication Pathway

HELIX-VAX
      ↓
Injection Site APCs
      ↓
Regional Lymphatics
      ↓
Draining Lymph Nodes
      ↓
Naive T Cell Priming
      ↓
Systemic Expansion
      ↓
Tumor Homing
      ↓
Tumor Elimination

Secondary Communication Pathway

APC
 ↓
Cytokines
 ↓
Innate Immune Cells
 ↓
Adaptive Immune Cells
 ↓
Memory Networks

3. MASTER PK/PD PROGRAM

4. PK-A1 BIODISTRIBUTION PROGRAM

Objective

Determine where vaccine material travels after administration.

Organs Evaluated

Biodistribution Score (BDS)

BDS =
Lymph Node Exposure
+
Immune Organ Exposure

-
Brain Exposure
-
Off-Target Exposure

5. PK-A2 LYMPHATIC TRAFFICKING

Objective

Determine efficiency of lymphatic targeting.

Desired Flow

Injection Site
 ↓
Lymphatics
 ↓
Draining Node
 ↓
APC Activation

Key Biomarkers

Lymphatic Efficiency Score (LES)

6. PK-A3 APC TRAFFICKING

Objective

Track movement of vaccine-loaded APCs.

Desired Pathway

Peripheral APC
 ↓
Antigen Uptake
 ↓
CCR7 Activation
 ↓
Lymph Node Migration
 ↓
T-cell Priming

APC Routing Index (ARI)

Measures:

• migration efficiency
• routing fidelity
• antigen delivery success

7. PK-A4 ANTIGEN PERSISTENCE

Objective

Determine duration of antigen availability.

Desired Window

Not too short:

• insufficient priming

Not too long:

• exhaustion risk

Antigen Persistence Categories

8. PD-A1 IMMUNE ACTIVATION KINETICS

Objective

Map pharmacodynamic activation over time.

Biomarkers

Activation Timeline

0–24 h
Innate Activation

24–72 h
APC Expansion

3–7 Days
T-cell Priming

7–21 Days
Adaptive Expansion

9. PD-A2 T-CELL EXPANSION KINETICS

Objective

Measure expansion dynamics.

Readouts

Expansion Score (ES)

ES =
CD8 Expansion
+
CD4 Expansion
+
Ki67

10. PD-A3 MEMORY FORMATION KINETICS

Objective

Determine long-term immune durability.

Memory Compartments

Memory Durability Index (MDI)

Measures:

• persistence
• recall potential
• booster responsiveness

11. CNS EXPOSURE PROFILE

Objective

Ensure minimal CNS exposure.

CNS Monitoring

Vaccine Material

Direct exposure

Cytokine Exposure

Indirect exposure

Activated Immune Cells

Immune trafficking

CNS Exposure Score (CES)

CES =
Direct CNS Exposure
+
Immune Cell CNS Entry
+
Cytokine CNS Exposure

Desired Outcome

Minimal exposure

Maximum safety

12. SCF SYSTEMS PHARMACOLOGY MODEL

Whole-Body Vaccine Response Model

Layer 1

Injection Site Biology

Layer 2

Lymphatic Biology

Layer 3

APC Communication Network

Layer 4

T-cell Expansion Network

Layer 5

Tumor Homing Network

Layer 6

Memory Maintenance Network

13. SCF IMMUNOLOGIC COMMUNICATION ATLAS

Communication Domains

Systems Communication Score (SCS)

SCS =
Routing Efficiency
+
Immune Coordination
+
Memory Stability

14. INTEGRATED PK/PD SCORE

Vaccine Systems Pharmacology Index (VSPI)

VSPI =
Biodistribution
+
Lymphatic Efficiency
+
APC Routing
+
Immune Activation
+
Expansion
+
Memory

-
CNS Exposure

Classification

15. GO / NO-GO CRITERIA

GO

✓ VSPI ≥ 85

✓ Strong lymphatic targeting

✓ Efficient APC routing

✓ Durable memory formation

✓ Minimal CNS exposure

CONDITIONAL GO

✓ VSPI 70–84

✓ Correctable deficiencies

NO-GO

✗ VSPI < 70

✗ Poor APC routing

✗ Excess CNS exposure

✗ Weak memory formation

16. OUTPUT FILES

DV08-01

Biodistribution Report

DV08-02

Lymphatic Trafficking Report

DV08-03

APC Routing Report

DV08-04

Antigen Persistence Report

DV08-05

Immune Activation Kinetics Report

DV08-06

T-cell Expansion Kinetics Report

DV08-07

Memory Formation Report

DV08-08

Systems Pharmacology Dashboard

17. STRATEGIC VALUE TO PROJECT HELIX-HTT

DV-08 establishes the complete pharmacologic behavior of HELIX-VAX across the whole organism.

This package defines:

• where the vaccine goes
• how long it persists
• how APCs route information
• how T cells expand
• how immune memory forms
• how neuroimmune safety is maintained

It provides the mechanistic bridge between efficacy (DV-06), safety (DV-07), and formal GLP toxicology studies.

STATUS

DV-08 — PK/PD, Biodistribution & Systems Pharmacology Report: COMPLETE

NEXT DELIVERABLE

DV-09 — GLP Toxicology & Safety Pharmacology Program

This module will establish IND-enabling toxicology, repeat-dose safety, immunotoxicology, reproductive toxicology considerations, local tolerance studies, dose-range finding, NOAEL determination, and regulatory-ready safety margins for HELIX-VAX advancement toward a Pre-IND package.