top-1 Antibody

Here’s a structured collection of FAQs tailored for academic researchers studying TOP1-targeting antibodies (TOP1-antibodies), synthesized from peer-reviewed literature and patent data:

Advanced Research Questions

How can researchers resolve contradictions in TOP1-ADC efficacy across preclinical vs. clinical models?

• Issue: Preclinical xenografts often lack tumor microenvironment complexity (e.g., stromal barriers, pH gradients).

• Strategy:

  • Use patient-derived organoids to model lysosomal pH variations affecting linker cleavage .

  • Validate payload release kinetics using mass spectrometry in 3D tumor spheroids .

What mechanisms underlie TOP1-ADC resistance, and how can they be circumvented?

• Key pathways:

  • TDP1-independent repair: Homologous recombination (HR) repairs TOP1-induced DNA damage, bypassing TDP1 inhibition .

  • Antigen loss: Tumor cells downregulate target antigens post-treatment .

Intervention: Combine TOP1-ADCs with HR inhibitors (e.g., PARP inhibitors) or dual-antigen targeting ADCs .

How can drug-to-antibody ratio (DAR) be optimized without compromising stability?

• Approach:

  • Evaluate site-specific conjugation (e.g., engineered cysteines) to maximize DAR while retaining binding affinity.

  • Screen linker-payload combinations for plasma stability (e.g., CL2A-SN-38 in IMMU-132) .

What novel targets are emerging for TOP1-ADCs beyond HER2/TROP2?

• B7-H3: Overexpressed in pancreatic/ovarian cancers with low normal-tissue expression .

• Nectin4: Validated in metastatic urothelial carcinoma; phase II trials show synergistic activity with enfortumab vedotin .

Research Gap: Mechanistic studies comparing antigen internalization rates (e.g., B7-H3 vs. CEACAM5) are needed to prioritize targets.