Antibody Drug Conjugates

What is 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

>$22B

Growing ADC Market: >$22B by 2030
with Large Deal Flow

>$4B

Growing ADC Market: >Global Trop2 market expected to
surpass $4 billion by 2026

There continues to be concerns of off-target effects and toxicities with current ADCs and their respective Payloads
Attribute Industry Standard Tubulin/DNA targeted payload Solution PH1 Splicing Modulator
Neutropenia Yes No
Peripheral neuropathy Yes No
Ability to generate neoepitopes Some High
Systemic exposure of payload

(consequence of Bystander effect and/or Cleavable linkers)

Pro

Killing of low and heterogenous target-expressing tumors

Con

Off-target and/ or Systemic toxicity

System Exposure to Payload

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
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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

System exposure of payload
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