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 Metastases | Irradiate 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)