Neuro-Oncology

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

  • Current cancer treatments have dose limiting toxicity reducing efficacy
  • Even “precision” medicine targets lack sufficient specificity to tumors
  • Most cancer drugs do not cross BBB to treat brain cancer
  • Current immune therapies do not target tumor associated macrophages (TAMs)

OUR SOLUTION

  • Opening the therapeutic window – increase MTD, better outcomes (e.g. sunitinib, TLR4 agonist)
  • Target & treat brain tumors
  • Durable effects – inside TAMs for up to 30 days

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

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

  • POC of tumor targeting across Blood Brain Barrier; leverage to select patients for HDTs
  • IND Q3 2021; initiate Phase 1 by end of 2021

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