Combotope Therapeutics – Q&A
This Q&A document describing Combotope Therapeutics’ platform, target strategy, antibody discovery process, IP position, development logic, and commercial framework.
1. Target Selection Strategy
Q: How are target proteins selected?
Target selection integrates multiple complementary data layers including gene expression datasets, surface proteomics, immunohistochemistry (IHC), literature curation, clinical pipeline benchmarking, and commercial landscape analysis. The goal is to identify surface-expressed proteins that are both therapeutically relevant and likely to contain aberrant O-glycosylation sites in cancer.
Q: What does “predicted O-glycosylation protein” mean?
These are proteins predicted to contain mucin-type O-glycosylation (Ser/Thr-linked GalNAc) based on validated bioinformatic tools such as NetOGlyc and Glyco.me, supported where available by mass spectrometry (MS) datasets and literature.
Q: How many targets are considered?
- Broad in silico universe: >900 predicted O-glycosylated surface proteins
- Actively prioritized internal list: ~50 high-value glycoproteins
Q: How are targets prioritized?
Prioritization is based on: - Therapeutic relevance and market potential - Clinical tractability - Prior validation in oncology (including abandoned ADC targets) - Predicted density and clustering of O-glycosylation sites - Epitope accessibility and membrane proximity
Q: Can partners define their own selection criteria?
Yes. Combotope can apply partner-defined biological and commercial filters (tumor type, internalization, exclusion lists, modality preferences) to generate a tailored prioritized target list.
2. Tumor-Specific Glycosylation & Selectivity
Q: Why focus on aberrant O-glycosylation?
Aberrant truncation of O-glycans (Tn and STn antigens) is a universal hallmark of cancer. These structures are nearly absent on healthy tissues but broadly present on tumor cells across solid malignancies.
Q: How does this improve selectivity?
Conventional antibodies bind protein epitopes regardless of glycosylation status and therefore often bind normal tissues. Combotope antibodies require both: - The correct protein backbone, and - The correct tumor-specific glycoform
This dual-recognition architecture provides intrinsic tumor selectivity.
Q: Is high tumor expression required?
Not necessarily. Because selectivity is driven by glycosylation state rather than protein abundance, therapeutic windows can be achieved even on proteins expressed in normal tissues.
3. Antibody Discovery Platform (iDEAL / SMART-Phage)
Q: What is the core discovery concept?
Combotope antibodies are discovered using a modular dual-specificity design: - VH domain: Selective glycan recognition (Tn or STn) - VL domain: Peptide/protein epitope specificity
Q: What libraries are used?
- Tn-focused glycan-binding VH libraries - STn-focused glycan-binding VH libraries - High-diversity murine VL repertoires for peptide selectivity
Q: What is the standard discovery workflow? 1. Target selection 2. Glycopeptide & glycoprotein production 3. Phage panning 4. Nanopore sequencing 5. Sequence clustering 6. scFv expression 7. Affinity & specificity validation 8. Data package delivery
4. Affinity, Kinetics & Functional Performance
Q: What affinities are achieved?
Combotope routinely identifies scFv clones with low nanomolar to picomolar binding affinities.
Q: Does affinity drop after IgG conversion?
No. In tested cases, IgG versions maintain or improve functional binding kinetics relative to scFv formats.
Q: Do Combotope antibodies internalize?
Yes. Internalization has been demonstrated on multiple glyco-targeted constructs and supports ADC and other payload-based modalities.
Q: Is cell-based binding validated?
Yes. Binding has been confirmed using wild-type cells, glycosylation-engineered cells, and tumor tissue sections.
5. Intellectual Property & Freedom-to-Operate
Q: What is protected?
- Glycan-selective VH domains - Dual-specificity antibody designs - Target-specific Combotope sequences - Discovery methodologies
Q: Are third-party licenses required for gene synthesis?
No licensing fees apply for standard gene synthesis services used to express discovered scFvs.
Q: Is humanization feasible?
Yes. Humanization has been successfully performed with minimal affinity impact in early testing.
Q: Has tumor-selective staining been demonstrated?
Yes. Tumor-selective IHC staining has been shown with minimal background staining in adjacent normal tissues.
6. Target Attrition & Portfolio De-Risking
Q: What is the typical hit rate?
Combotope identifies high-affinity scFvs to at least one epitope on >80% of screened glycoprotein targets.
Q: Where does attrition mainly occur?
Not in discovery, but during biological relevance filtering, functional efficacy testing, and in vivo validation.
Q: How is attrition mitigated?
- Multiple glycosylation sites per target - Multiple targets per indication - Parallel in vitro and in vivo screening strategies
7. Commercial Framework (Generic Model)
Q: How does the collaboration structure typically work?
- Nomination of one or multiple glyco-targets - Discovery and data package delivery - Partner evaluation window - STOP/GO progression to option or license
Q: What payments are typical?
- Target nomination fees - Option fees - Milestone payments (preclinical → clinical → regulatory) - Tiered sales royalties
Q: What exclusivity options exist?
- Antibody-only exclusivity - Antibody + modality exclusivity - Epitope-level exclusivity - Full target exclusivity
8. Modalities Supported
Combotope antibodies are compatible with: - ADCs - Bispecifics - CAR-T / CAR-NK - Radioligand therapy - Immune engagers