Co-targeting cancer and the tumor immune microenvironment with
Conditionally Activated-Small Molecule Drug Conjugates (CA-SMDCs)TM
CA-SMDC Therapeutics
Cancer metabolism and immune escape are major hallmarks of cancer.
This conditional reprograming of tumors versus normal tissue empowers the MaveriX targeting
strategy to treat a broad range of solid tumors.
IMPACT-2X is a proprietary hydroxylase-releasable masking technology used to generate a portfolio
Conditionally Activated Small Molecule Drug Conjugates or CA-SMDCs.
CA-SMDCs are designed to be stable and inactive until they engage tumor-associated hydroxylases
which trigger CA-SMDC fragmentation to deliver an active payload or drug selectively to the tumor.
The targeted delivery of DNA damaging cytotoxic and immunogenic payloads through CA-SMDCs has
the potential to achieve anti-tumor activity in multiple cancer histologies while co-targeting immune suppressive cells that contribute to immunotherapy resistance.
Opportunities for CA-SMDCs in Cancer Immunotherapy
CA-SMDC therapeutics targeting defined pathways and/or cells capable of immune modulation are expected to
substantially improve the efficacy and safety of cancer immunotherapy
Key advantages of CA-SMDC therapeutics as a targeting strategy are:
- Remodel immunogenically “cold” tumors to overcome resistance to
immunotherapy including immune checkpoint inhibitors - Stimulate innate and adaptive immune responses to destroy cancer
- Target immunosuppressive cells in the tumor immune microenvironment
that promote tumor growth and metastasis - Single-agent activity in multiple solid tumors and mechanistic rationale
enabling combination immunotherapy
CA-SMDC Payload Selection
IMPACT-2X is a proprietary hydroxylase-releasable masking technology used to generate
Conditionally Activated Small Molecule Drug Conjugates or CA-SMDCs.
Our CA-SMDC pipeline consists of a drug or payload conjugated to a Pro-XACT ‘molecular mask’ by a
hydroxylase-cleavable linker.
CA-SMDCs are designed to be stable and inactive until they engage tumor-associated hydroxylases
which trigger CA-SMDC fragmentation to deliver an active payload or drug selectively to the tumor.
Payloads have been selected for single-agent anti-tumor activity but have the potential to overcome
tumor immune suppression and stimulate both innate and adaptive immune responses
for combination immunotherapy.
Hydroxylase Biology in Cancer
CA-SMDC therapeutics exploit the high levels of hydroxylase activity that are unique to cancer and
the tumor immune microenvironment to more effectively localize treatment to the tumor,
while limiting activity in healthy tissues.
Hydroxylases play an essential role in many aspects of normal physiology, but specific hydroxylases
are de-regulated and over-expressed to a high frequency in virtually all types of tumors,
driving tumor growth, invasion, metastasis, and immune suppression.
Specific hydroxylases are targets for well validated immune suppressive metabolic pathways in
cancer and therefore represent a unique opportunity to overcome metabolic redundancy associated
with tumoral immune evasion.
Biomarker-Driven CA-SMDC Therapeutics
MaveriX combines transcriptomic and proteomic co-expression analysis of oncogenic and
immunogenic markers in cancer versus normal tissue to identify novel metabolic targets
that drive tumor growth, metastasis, and immune suppression.
Our translational approach includes creating novel assays as companions to our development
candidates in order to identify patients that will gain therapeutic benefit from treatment.
PDX = Patient-Derived Xenograft Model; TMA = Tumor Tissue Microarray; CDx = Companion Diagnostic,
T = Tumor tissue, M = Metastasis, N = Normal tissue
