STRC h09 Phase 4o AF-M Nanobody Method Transfer 2026-04-27
Harvey 2026 imports as a cautionary secondary interface-score gate for h09; no new VHH therapy and no S-tier movement.
Problem
The Bio+AI Daily post highlighted Harvey et al. 2026: AF-M screening of synthetic VHH/nanobody sequences against GPCR MRGPRX2 found experimentally validated nanomolar binders. The question for STRC is whether this creates a new therapeutic hypothesis or strengthens an existing one.
Method
- Read the post first, before paper/code.
- Retrieved and MinerU-parsed the Nature Communications paper and selected supplementary files.
- Reviewed h09 and h26 hubs/logs because these are the active protein-interface hypotheses.
- Reviewed the GitHub scorer as a method reference and filed a tool card.
Results
| Candidate use | Decision | Rationale |
|---|---|---|
| New STRC nanobody therapy | Reject / do not register | Delivery, immunogenicity, expression, and target-class risks are high; paper does not validate non-GPCR targets. |
| h26 homodimer rescue | Not actionable now | h26 currently lacks a passing structural candidate; Harvey’s method does not rescue failed non-GPCR homodimer designs. |
| h09 method import | Keep as secondary gate | h09 already uses AF3 interface scores and negative controls; Harvey gives a concrete parser/metric recipe and a strong warning not to interpret scores as Kd. |
Numbers imported
| Finding | Value | Source |
|---|---|---|
| GPCR top-5% precision | 0.93-1.0 | 2026-harvey-afm-nanobody-gpcr |
| Soluble/non-GPCR top-5% precision | ⇐0.22 | 2026-harvey-afm-nanobody-gpcr |
| Prospective screen scale | 10000 VHH sequences | 2026-harvey-afm-nanobody-gpcr |
| Above-threshold hits | 179 / 10000 | 2026-harvey-afm-nanobody-gpcr |
| Validated binders | ranks 1, 5, 7 | 2026-harvey-afm-nanobody-gpcr |
| Validated Kd range | 20-200 nM | 2026-harvey-afm-nanobody-gpcr |
| Interface contact cutoff | ⇐10 A C-alpha distance | 2026-harvey-afm-nanobody-gpcr |
Phase skeleton
Only run this if Phase 4m/4k results are ambiguous enough that a method cross-check is worth the extra work.
| Phase | Purpose | Output | Gate |
|---|---|---|---|
| 4o | Literature/method import | This note | No tier movement |
| 4p | Parser adaptation | tail91 AF3/AF-M interface PAE, pLDDT, pDockQ, model support vs matched negative controls | Method confidence only; cannot promote tier |
| 4q | Optional VHH reagent screen | If ever needed, VHHs as assay reagents against TMEM145/STRC, not as therapy | Requires wet-lab validation before any hypothesis promotion |
Verdict
- Outcome: METHOD-IMPORT.
- Interpretation: useful as a discipline layer for interface-score parsing and negative controls; not useful enough to create a new hypothesis.
- Limitation: h09 is not a GPCR nanobody problem. The paper’s own non-GPCR benchmark is the load-bearing warning.
Ranking delta
- Hypothesis h09: tier tentative-S → tentative-S | mech 5 → 5 | deliv 4 → 4 | misha_fit 3 → 3.
- Next step unchanged: Phase 4m / Phase 4l / Phase 4k remain the active gate closers.
- Evidence added: method note and tool card. No tier movement.
Connections
[part-of]h09 hub[source]2026-harvey-afm-nanobody-gpcr[see-also]MRGPRX2 AF-M screen[see-also]STRC h09 Phase 4n Avidity Monte Carlo 2026-04-26[see-also]avidity-and-dimers