Ketchem Biotherapeutics Consulting LLC

ketchemconsulting.com

AbLead

Developability by Design

Antibody sequence and structure analysis to evaluate, rank order, and engineer biotherapeutics.
Identify and engineer 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 .
60% Phase 2 antibody candidates with developability issues .
$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.

Biotherapeutic optimization is well worth the initial investment of time and resources

Biophysical Properties

Stability engineering greatly improved overall biophysical properties ...

Stable Cell Titer

... and more than doubled stable cell titer .

Serum Half Life

Developability optimization markedly improved serum half-life .

Empirical validation proves the case for early stage developability optimization.

Capabilities

01

Rank Order Analysis & Lead Selection

Evaluate antibody sequences across a wide range of developability attributes to rank order and select lead candidates.

  • KBC Score: Aggregate developability score weighted by severity allows for cross-trait rank ordering and targeted lead selection.
  • Lead Panel Selection: Rank order and select candidates based on multiple thresholds and filtering criteria.
  • Fv Features: Automated analysis of:
    • Germline Mapping: Closest V-Gene identity and origin mapping.
    • Nearest Neighbor: Identification of nearest sequence neighbors within an antibody sequence space
    • CDR Lengths: Evaluate CDR lengths and CDR Sum.
    • Structural Stability: AbLang, AbLang2, and IgBert machine learning-based likelihood scores (Full Fv & Framework) predicting potential stability impacts .
    • Salt Bridge: Detection of disrupted HC-CDR3 Salt Bridges that impact CDR stability and efficacy .
    • Surface Properties: Surface Hydrophobicity (SPH), Positive/Negative Charge Patches (SPP/SPN), and Fv Charge Dipole (SPCD) calculation .
    • Cysteine Analysis: Identification of unpaired, missing, or unusual cysteines, ensuring stable fold and disulfide pairing.
    • Potential Post-Translational Modifications: Deamidation, isomerization, oxidation (Met/Trp), N-glycosylation, hydrolysis, and fragmentation scanning .
    • Humanness (OASign): Log-likelihood scoring against 130M+ human sequences.
    • Isoelectric Point (pI): Avoid serum pH instability and select for optimal formulation.
02

Engineering

Design and evaluate optimization variants and humanizations directly within the application workspace.

  • Observations Logs: Record past IMGT-positioned residue observations to aid lead selection and engineering based on experimental history.
  • Batch Assembler: Quickly assemble full-length modalities from multiple Fv-containing entries using standard or user-specific custom parts.
  • Multispecific Assembler: Design complex multispecific formats (bi-specifics, CrossMabs, scFvs, etc.) with pre-configured linkers, heterodimerization domains (Knobs-into-Holes), and crossover parts.
  • Fv Pair Extraction: Automatically dissect and pair VH/VL variable domains from multispecific or full-length IgG antibodies.
  • Humanization Workspace: Germline template or Sapiens-based humanization with controlled site exclusions allows for design and evaluation of humanized candidates.
  • Isoelectric Point Engineering: Shift the pI of a candidate to improve developability and formulation stability while limiting impacts on stability and humanness.
  • Engineering Panel: Enter and track desired mutation to repair stability violations, replace free cysteines, repair potential PTMs, modify humanness, and any other desired characteristic to optimize developability properties.
  • Build Models: Generate 3D structural Fv models using ABodyBuilder2 .
03

Visual Analysis

Interactive dashboards and visualizations for sequence alignment, diversity, structure mapping, and variant selection.

  • Numbering Schemes: Aho, IMGT, Martin, and Kabat numbering assignment .
  • CDR Detection: Aho, IMGT, Martin, Kabat, and North CDR region detection.
  • Sequence Alignments: Numbering system-based alignments for direct residue comparisons.
  • Clading / Dendrograms: Ensure sequence diversity amongst lead candidates.
  • Liabilities & 3D Structure: Interactive in-browser Molstar 3D structure and structural liability mapping with MOE SVL export capability.
  • Humanness: Visual evaluation of sequences against human germlines, with per-residue OASign, AbLang Diff, and PFA.
  • Positional Frequency: Analysis of per-residue positional frequencies by germline to aid engineering selections.
  • LLM Residue Analysis: Language model likelihood calculations to assess mutation tolerability.
  • Mutation Grid: View and compare mutational differences between selected entries.
  • Physical Properties View: Comparative dashboards for panel-wide physical properties.
  • Solvent Exposures: Visual evaluation of per-residue solvent accessibility with included sidechain and per atom exposures.
  • Clinical Comparison: Comparison of entry evaluations against the Jain clinical molecule set.
  • PLAbDab Search: Perform an internal search of the PLAbDab database for potential literature or patent similarity to the quesry sequence.

References