D6-B483

Oncology Pipeline Addresses Unmet Needs

TUMOR-ASSOCIATED MACROPHAGES:
Solid Tumors Evade Immune System Due to Suppressive Cells; Drugs Fail to Target These Cells

THE NEED

  • Even current “precision” medicine lacks the ability to only treat cancer cells, often killing healthy cells which leads to potentially toxic side effects, making the treatment less effective
  • Most cancer drugs are unable to cross the blood brain barrier (BBB) to treat brain cancer
  • Current immune therapies do not target tumor associated macrophages (TAMs), specific cells involved with the progression, spread, and inflammatory response of cancer

OUR SOLUTION

  • HDTs target inflammatory cells associated with cancer, delivering drugs only to tumors throughout the body, including the brain

  • Reduce side effects and allow for higher doses of drugs to reach cancer cells, making treatments more effective

  • Durable effects HDTs are retained inside TAMs – for up to 30 days, while healthy cells do not take in the drug

Approaches:

1

2

3

Activate TAMs
(heat tumors)
Inhibit MetastasesIrradiate Tumors
(TAM reservoir)

Tuning Our HDT to Optimize TAM Targeting

Construct Optimization: Single IV Dose in MC38 (Colon) Mouse Model

Targeting to Tumors:

  • HDs optimized to achieve efficient uptake by M2 TAMs
  • >60% of all M2 TAMs contain HD6 after single I
    V dose
  • M1, mMDSCs and gMDSCs provide secondary targets (all other cells < 5%)

HDTs in Synthesis or Completed (SAR Design) – 21 Compounds

Cleland 2020; Liaw 2020

Preclinical Validation of Selective Brain Tumor Targeting and Persistence

Construct Optimization: Single IV Dose in MC38 (Colon) Mouse Model

Human Validation Strategy

D6-B483 Phase 1: Patients with GBM and Brain Metastases

  • POC of tumor targeting across Blood Brain Barrier; leverage to select patients for HDTs
  • Initiate Phase 1 in 2023

*Orthrotopic GBM (GL-261-luc)   
High levels of reactive microglia/macrophage analogous to human GBM (Szulzewsky 2015)