US biotech IDEAYA Biosciences has secured US FDA clearance for an Investigational New Drug (IND) application for IDE034, a potential global first-in-class bispecific antibody-drug conjugate (ADC) designed to simultaneously target B7H3 and PTK7 to deliver a TOP1 cytotoxic payload. The San Francisco-based firm plans to begin enrollment in the Phase 1 clinical trial from Q1 2026 focusing on patients with solid tumors known to express B7H3 and PTK7, including lung, colorectal, head and neck and ovarian/gynecological cancers.
Based on positive preclinical data in tumor models, IDEAYA plans to assess IDE034 both as a monotherapy, and in combination with the firm’s pipeline candidate IDE161, a small molecule PARG inhibitor.
IDE034’s multi-faceted mechanisms
Both B7H3 and PTK7 are surface proteins highly expressed in a range of solid tumors and associated with tumor progression, metastasis, and poor prognosis. B7H3 is an immune checkpoint molecule that contributes to immune evasion and tumor aggressiveness, while PTK7 is a pseudokinase involved in cell migration, invasion, and chemoresistance.
IDE034 belongs to a new wave of bispecific ADCs aiming to enhance tumor selectivity by requiring co-expression of two surface markers for optimal payload delivery. IDEAYA is aiming to leverage the co-expression of B7H3 (CD276) and PTK7 in multiple tumor types, with data from the Human Protein Atlas database indicating co-expression of the two targets in lung, colorectal, and head and neck cancers at around 30%, 46% and 27%, respectively. These findings are backed by preclinical data
The dual targeting of B7H3 and PTK7 offers several potential R&D advantages: enhanced tumor specificity with reduced off-tumor toxicity thanks to a narrower delivery focused on cells expressing both receptors; reduced resistance since there is less likelihood of tumor escape via compensatory mechanisms; increased payload concentration, ADC internalization, and therefore payload release; and a broader indication reach.
TOP1 payload and PARG combination strategy
IDE034 carries a topoisomerase 1 (TOP1) inhibitor payload, a cytotoxic molecule that produces replication-associated DNA damage and increased dependency on DNA repair pathways, particularly upstream steps involving PARG, a key component of poly(ADP-ribose) (PAR) metabolism. PARG inhibitors block the repair of DNA damage by preventing the removal of poly(ADP-ribose) chains, thereby potentiating the cytotoxic effects of DNA-damaging agents such as TOP1 inhibitors. This mechanistic link provides the translational rationale for IDEAYA’s unique plan to pair its TOP1 ADCs with the company’s PARG inhibitor, IDE161.
The combination of IDE034 with ID161 was found to increase the durability of response and delay tumor reemergence. Based on these findings, IDEAYA hypothesizes that the DNA damage induced by TOP1 payloads appeared to sensitize tumors to PARG blockade, with preclinical findings to be published in 2026.
Positioning within the ADC innovation landscape
IDEAYA exercised an option to the exclusive global rights to IDE034 under a licensing deal with China-based Biocytogen announced in November 2024. The molecule is IDEAYA’s 7th pipeline candidate to reach the clinical trial stage, and second TOP1-targeted ADC. The firm’s other ADC candidate is the DLL3-targeted IDE849, with rights licensed from China-based Hengrui Pharma.
IDEAYA is seeking to differentiate its pipeline in a competitive yet rapidly evolving ADC field increasingly defined by multi-target ADCs. B7H3 targeting has gained traction (e.g. MacroGenics, Daiichi Sankyo), but no bispecific B7H3/PTK7 ADC exists in clinical development. Meanwhile, PTK7 is a validated but underexploited target, with only a limited number of ADCs reaching clinical evaluation. Several related bispecific ADCs (e.g., targeting PTK7 and EGFR, or cMET and B7H3) are in preclinical or early clinical evaluation, demonstrating the field’s momentum.
TOP1 payloads have become a competitive space following the market approvals for Daiichi/AstraZeneca’s Enhertu (trastuzumab deruxtecan) and Gilead’s Trodelv (sacituzumab govitecan). However, bispecific delivery of TOP1 remains novel. Furthermore, IDEAYA’s application of its understanding of synthetic lethality and post-PARP pathways (PARG) to explore the PARG-TOP1 ADC axis is an area with few established competitors, pushing ADCs beyond cytotoxicity toward pathway-driven synthetic lethality and offering first-in-class potential. If IDE034 reproduces its preclinical activity in humans, particularly in combination with IDE161, it could define a new mechanistic subclass of dual-target TOP1 ADCs with enhanced durability.