Ketchem Biotherapeutics Consulting LLC

ketchemconsulting.com
AbRankOrder

Developability by Design

Advanced structural rank ordering and lead optimization for biotherapeutics.
Identify stable, manufacturable candidates before you invest in the lab.

The Cost of Selecting the Wrong Lead

Pursuing a poorly behaving antibody is one of the most expensive mistakes in drug discovery.
Sequence and structural filtering minimizes this risk.

$11K-$16K Average daily out-of-pocket cost for the early development of a biotherapeutic lead candidate .
50% Commercial antibodies fail basic characterization standards .
$800k Lost value per day of delay due to poor developability .
"The cost of engineering an antibody at the discovery stage is significantly lower than the cost of optimizing process and formulation at the development stage ."
Application of rank ordering and stability optimization is a proven method for antibody therapeutic design .
Randal R. Ketchem, Ph.D.

Computational Analysis & Output

Fv Attributes

  • Germline: V-Gene identity and origin mapping.
  • Humanness: Log-likelihood scoring against 130M+ human sequences.
  • Numbering: IMGT/Kabat/Martin/AHo numbering assignment.
  • CDR Detection: IMGT/Chothia/Kabat/North CDR region detection.

Lead Selection

  • KBC Score: Aggregate developability score weighted by severity allows for cross-trait rank ordering and targeted lead selection.
  • Optimization Engineering: Detailed per residue liabilities allows for targeted optimization designs.
  • MOE Liability Mapping: Export of CCG MOE SVL files quickly indicates liability positions on the antibody structure.

Liability Scanning

  • Chemical Liabilities: Deamidation, Isomerization, Oxidation (Met/Trp), N-GLyc, Hydrolysis, Fragmentation .
  • Stability Motifs: Disrupted HC-CDR3 Salt Bridge.
  • Isoelectric Point: Avoid serum pH instability and select for optimal formulation.

Structural Stability

  • AbLang & AbLang2: Machine learning-based likelihood scores (Full Fv & Framework) predict potential impacts to stability .
  • Cysteine Analysis: Identification of unpaired, missing, or unusual cysteines.

Surface Properties

  • SPH: Surface Hydrophobicity (Aggregation and stickyness risk).
  • SPP / SPN: Positive and Negative charge patches (Clearance/Viscosity).
  • SPCD: Fv Charge Dipole calculations.

Fv Optimization

  • Stability Violation Repair: Stability may impact titer, yield, aggregation, particulation, low pH stability, and more.
  • PTM Liability Repair: Stress and storage may impact PTM formation, leading to potential loss of efficacy.
  • Missing or Unusual Cysteine Repair: Free cysteines can for cross-chain disulfides for undesired pairings.
  • Surface Repair: Surfaces may be repaired while seeking to limit the introduction of instabilities or PTMs.

References