ONCOLOGY
ANTIBODY DRUG CONJUGATES (ADCs)
WHAT ARE ADCs?
- ADCs are a class of anti-cancer agents that combine selectivity of monoclonal antibodies with the cytotoxic potential of small-molecule chemotherapeutics
- ADCs work by targeting
- An Antigen: protein targets that are present on cancer cell surface
- With an Antibody: a large protein made by the immune system to seek out and destroy non-self antigens
- Using a Linker: a chemical moiety that serves as a bridge and can be designed to immolate in the tumor cell/environment
- This combination results in delivering a Payload/Toxin: a small molecule with sub-nanomolar potency against target cells
WHY USE ADCs?
- Chemotherapies and targeted small molecules delivered systemically must be dosed until the target at the tumor site is saturated
- Inability to focus treatment to the cancer target results in a) exposure to higher doses and b) off-target toxicity to other organs
- ADCs reduce systemic exposure of payload by combining
- cancer-specific antigens
- high target specificity, affinity, and favorable pharmacokinetics of mAbs
- linkers responsive to tumor environment
- Therefore, ADCs focus therapeutic delivery to cancer over normal cells improving the therapeutic index
Growing ADC Market:
>$22B by 2030 with Large Deal Flow
Global Trop2 market expected to surpass $4 billion by 2026
Pro: Killing of low and heterogenous target-expressing tumors
Con: Off-target and/ or Systemic toxicity
Peak Bio has a platform of Best-in-Class Approaches to expand the utility of ADCs
CURRENT ADC APPROACH
- Over 90% of current ADC payloads target tubulin or DNA (Processes essential to dividing cancer cells or their DNA)
- There is emerging resistance to these payloads
- Industry standard payloads are still associated with significant toxicities (see table above)
- Substrates of MDR(ABC) Transporters (Emerging drug resistance mechanisms)
OUR NOVEL, IMMUNO-STIMULATORY PAYLOAD APPROACH
Spliceosome Modulation (PH-1)
- Targeting proper splicing of introns results in mRNA decay depriving cancer cells of essential proteins and mis-spliced proteins
- Creates neoepitopes for immune cells to target well after the initial “chemotherapy” is delivered
DNA mismatch repair (MMR) interference (PH-5)
- Prevent cancer cells from repairing mistakes during active DNA replication, thereby fixing the errors in translated proteins (neoepitopes)
Immune Suppression (PH-6)
- Killing tumor cells and pro-tumor immune cells that have been coopted
WHAT MAKES OUR SOLUTION BETTER?
- Enhances tumoricidal activity beyond cytotoxicity creating a potential Best-in-Class approach to treating cancer
- Engaging the host response (T and B cells) can co-evolve and can counter resistance mutations
- Payloads that act as poor substrate for MDR Transporters
- Immune memory can re-engage when treated cancers reoccur
Our Approach: Generation of Novel Toxins
Spliceosome Modulation (PH1)
- Disrupts alternative Splicing
- Deprives cancer cells of essential survival and growth factors
- Causes accumulation of mis-spliced proteins inducing tumor cell death
- Accumulates neoantigens recognized by immune cells as foreign proteins
- Synergizes with checkpoint inhibitors that alleviate suppression of immune cells
Novel or Validated Targets
Differentiated ADCs with improved safety/ efficacy profiles
Clinically validated Target (Trop2)
- Superior linker stability compared to an FDA approved competitor
- Superior specificity to cancer cells and unique ability to generate neoepitopes and synergizes with I/O therapies
- Anti-tumor immune memory
- Wide safety margin in non-human primate tox study
- IND-lead candidate chosen & 18-24 Month FIH
- De-risked antibody manufacturability
Our Solution: Immunostimulatory Payloads
Pros
- Killing of low and heterogenous target-expressing tumors
- Reduced off-target and/or systemic toxicity as catabolites are impermeable
- Long lasting immune memory
Cons
- May require alleviation of checkpoint inhibited immune cells in some tumors