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Bundled VHH Frameworks

This folder contains bundled VHH framework YAML records loaded by the esmfold2-pipeline framework registry. They are available through binder.scaffold: vhh and can be selected by alias, canonical name, or --frameworks all.

Each YAML record is a single-domain framework template with IMGT-derived CDR placeholders:

{cdr1}, {cdr2}, {cdr3}

The core panel is selected for practical framework exploration rather than for target-specific transfer. Active YAML records are limited to clinically exposed VHH frameworks with public RCSB coordinate support. The source therapeutic target is useful provenance, but users should assume the CDRs will be diversified for a new target.

Primary sequence source: Thera-SAbDab sequence/structure download, accessed 2026-06-17. The downloaded table reports sequence release PL132 with clinical-stage field dated Feb '25.

Core Panel

Alias Canonical name Source therapeutic Clinical provenance Inferred annotation Rationale
caplacizumab_vhh caplacizumab_framework_vhh Caplacizumab Approved Nanobody, VWF alpaca IGHV3-3 / IGHJ4 First approved VHH/Nanobody medicine, exact structural coverage, long native CDR3.
ozoralizumab_tnf_vhh ozoralizumab_tnf_framework_vhh Ozoralizumab TNF-binding domain Approved in Japan, TNF/albumin Nanobody alpaca IGHV3-74 / IGHJ5 Approved VHH therapeutic with exact structural coverage and short native CDR3. The YAML uses the TNF-binding domain, not the albumin-binding domain.
vobarilizumab_il6r_vhh vobarilizumab_il6r_framework_vhh Vobarilizumab IL-6R-binding domain Phase II clinical Nanobody with exact structure alpaca IGHV3S53 / IGHJ5 Clinically exposed, structurally covered IL-6R domain with a distinct inferred V gene. Included despite discontinuation because it is useful framework diversity.

Coordinate Files

Processed framework-only mmCIF templates are vendored beside the active YAMLs. The original RCSB downloads are retained under reference_structures/ with the same filenames. The processed templates use one synthetic chain whose sequence is the YAML VHH sequence with {cdr1}, {cdr2}, and {cdr3} removed. Antigen chains, additional VHH domains, waters, ligands, tags, and CDR atom rows are removed.

When multiple candidate structures were available, the selected reference was the best-resolution entry that matched the YAML framework sequence, with coordinate completeness considered for retained framework residues.

Framework Processed template and RCSB reference
caplacizumab_vhh caplacizumab_vhh_7EOW.cif
ozoralizumab_tnf_vhh ozoralizumab_tnf_vhh_8Z8M.cif
vobarilizumab_il6r_vhh vobarilizumab_il6r_vhh_7XL0.cif

Additional coordinate-backed clinical backfill reference structures are vendored under reference_structures/ for future curation, but are not registry frameworks until their YAML templates have been sequence/CDR-validated:

Candidate Vendored coordinate
envafolimab_vhh reference_structures/envafolimab_vhh_5JDS.cif
gefurulimab_c5_vhh reference_structures/gefurulimab_c5_vhh_8COH.cif
ciltacel_bcma_nb1_vhh reference_structures/ciltacel_bcma_nb1_vhh_8HXQ.cif
ciltacel_bcma_nb2_vhh reference_structures/ciltacel_bcma_nb2_vhh_8HXR.cif

YAML Shape

The VHH YAMLs intentionally differ from the scFv framework records:

id: caplacizumab_vhh
canonical_name: caplacizumab_framework_vhh
modality: vhh
format: template
template: "FR1{cdr1}FR2{cdr2}FR3{cdr3}FR4"
cdr_lengths:
  cdr1: {min: 7, max: 9}
  cdr2: {min: 7, max: 9}
  cdr3: {min: 18, max: 24}

There is no linker and no light chain. The template field represents one VHH domain only. The cdr_lengths windows are deterministic around the observed source CDR lengths:

  • CDR1 and CDR2: observed length +/- 1, with a lower bound of 5.
  • CDR3: observed length +/- 3, with a lower bound of 5.

Multispecific Records

Several clinical VHH products are multispecific and include an albumin-binding VHH for half-life extension. The core records select the disease-targeting domain from each source product:

  • ozoralizumab_tnf_vhh uses the TNF-binding domain, not the albumin binder.
  • vobarilizumab_il6r_vhh uses the IL-6R-binding domain, not the albumin binder.

Albumin-binding VHH frameworks may be useful later as optional half-life extension scaffolds, but they should not dominate the core panel because the same or related albumin-binding domains recur across multiple programs.

Exclusions For The Core Panel

The following categories were intentionally left out of the core VHH set:

  • VL-only single-domain antibodies such as lulizumab and placulumab.
  • Conventional VH/VL antibodies with camelid-origin heavy chains.
  • Veterinary-only VHHs.
  • Records with unclear sequence provenance or TBC status.
  • CAR-T VHH YAMLs until the individual VHH domains are curated and sequence/CDR-validated separately from patent, regulatory, or coordinate sequence listings.

Sequence-only VHH records without exact public coordinates are kept under legacy/ for provenance. They are not included in --frameworks all.

Runtime Contract

VHH records are loaded through the VHH registry, separate from the scFv registry, because VHH templates use cdr1, cdr2, and cdr3 placeholders instead of the scFv hcdr* and lcdr* placeholder set. During design, the sampler generates one mutable run per VHH CDR in template order and keeps all framework residues fixed.

Final CSV exports map the three designed VHH CDR sequences to heavy-chain columns:

hcdr1, hcdr2, hcdr3

VHH exports intentionally do not include light-chain CDR columns.