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

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

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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