ADC+DDR

IDEAYA’s ADC strategy focuses on identifying tumor surface proteins that remain consistently expressed from early disease through metastatic progression—creating stable and reliable entry points for targeted therapy.

These proteins are leveraged as precision delivery targets—enabling selective delivery of a potent cytotoxic payload into tumor cells while sparing normal tissue.

By linking a TOP1 inhibitor payload to a tumor-targeting antibody, IDE849 delivers DNA-damaging therapy with high selectivity, maximizing therapeutic index while minimizing free payload exposure.

This delivery strategy is designed not only to drive tumor cell killing, but also to serve as the foundation for a broader approach that induces synthetic lethality when combined with DNA repair inhibition.

One area where this approach may be particularly impactful is for DLL3-expressing neuroendocrine carcinomas (NECs), including small-cell lung cancer, where:

• Tumors are initially responsive to cytotoxic therapy
• Durability is limited by tolerability and resistance mechanisms

Using ADCs as monotherapies, IDEAYA aims to preserve strong response rates while reducing toxic burden—enabling more sustained treatment benefit. 

Cell surface proteins like B7-H3 and PTK7 present a promising bispecific targeting opportunity.

Although B7-H3 has limited expression in normal tissues, PTK7 can be present on some healthy cells, which could limit the therapeutic window of traditional single-target ADCs.^2-4

To overcome this, IDEAYA is advancing IDE034, a bispecific ADC, that preferentially targets both surface proteins simultaneously.

Because B7-H3 and PTK7 rarely occur together on healthy tissue—but are highly co-expressed in colorectal, lung, and head and neck cancers, among other types of cancer—this strategy maximizes tumor-specific binding while sparing healthy organs.

A key component of IDEAYA’s ADC+DDR strategy is the combination of TOP1-based ADCs with PARG inhibition to create a synthetic lethal interaction.

When a TOP1 ADC delivers its payload, it triggers DNA damage and replication stress within tumor cells, characterized by:⁵

• Formation of TOP1 cleavage complexes, where the TOP1 enzyme becomes trapped on DNA, creating DNA lesions that require repair
• Accumulation of stalled DNA replication forks at sites of blocked repair, further disrupting tumor cell proliferation

To survive this stress, cancer cells depend on PARG, an enzyme that directly facilitates DNA repair by hydrolyzing poly(ADP)-ribose chains that accumulate at DNA damage sites and stalled replication forks.⁶ By inhibiting PARG, IDE161 blocks this recovery process, trapping the tumor cell in a state of unresolved DNA damage and aiming to:

• Drive synthetic lethality: prevent repair of the DNA damage induced by the ADC payload, pushing tumor cells toward cell death
• Overwhelm repair capacity: sustain replication stress until the cell can no longer maintain genomic integrity
• Shut down resistance pathways: disable key escape mechanisms tumors use to survive and develop resistance to existing TOP1-based therapies  

By inhibiting PARG, IDE161 is designed to prevent tumor cells from repairing ADC-induced DNA damage, engineering a biological dead-end that drives sustained tumor cell death.