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Immune Checkpoint Antibodies: Specialized Services for Unique Molecules

Monoclonal antibody therapeutics targeting immune checkpoint inhibitors or activators are a heterogeneous class of T cell modulating drug. Examples of monoclonal antibody therapeutics interacting with T cell signaling receptors include Ipilimumab (αCTLA4, or cytotoxic T-lymphocyte 4) as well as Nivolumab and Pembrolizumab (αPD-1, or programmed cell death protein 1). Examples of immune checkpoint activators targeted by agonist mAbs include αGITR and αOX40. Although the targets of these molecules are different, the goal is the same: modulate T cell reactivity to tumors by blocking inhibitory pathways or enhancing stimulatory pathways.

The individual program required for development, characterization, and lot release as well as for biosimilarity assessment of immune checkpoint inhibitors needs to be tailored to the specific molecule. As a global company with extensive scientific expertise, we guide clients from discovery to approval and provide continuity for their entire program. An example program for anti-immune checkpoint inhibitors can be seen below:

Development and Characterization Package for Anti-Immune Checkpoint Inhibitors

Tumor Models for Drug Discovery

Mouse models for efficacy, PK, safety, MTD, MOA
More than 20 characterized syngeneic models
Humanized knock-in models where the mouse gene is replaced with a human gene (e.g., CTLA-4)
Humanized mice: human immune cells engrafted into immunodeficient mice
Physicochemistry/Structure Function - Biological Activity Assays
  • Protein quality and purity
  • Molecular weight determination by MS
  • Amino acid sequence by LC-MS/MS and Edman degradation
  • Glycosylation and other PTMs analysis
  • Physicochemical properties
  • Aggregation analysis by SEC-MALS and AUC
  • Pathway-specific reporter assays
  • Antibody-dependent cell-mediated cytotoxicity (ADCC) assay
  • Apoptosis assay
  • Flow cytometry binding assay
  • Cell sorting
  • Fc receptor assays
Preclinical In Vivo Package Preclinical/Clinical Laboratory Support Package
  • Pharmacology/pharmacodynamic PK/PD study
  • Four-week comparative toxicity study
  • Tissue cross-reactivity
  • Bioanalysis and pharmacokinetic (PK) analysis
  • Immunogenicity
  • Pharmacodynamic (PD) (e.g., flow cytometry, ex vivo recall response, antigen challenge models, cytokine analysis)
  • Receptor occupancy
Formulation Lot Release and Stability Testing
  • Preformulation
  • Stress studies
  • Product formulation (or reformulation)
  • Pilot studies
  • Release/stability methods development and validation
  • Routine testing
  • Stability testing including accelerated stress condition testing with mode of action assays

Along with our assay experience, Charles River is also able to help support our clients' regulatory questions and make sure that their program meets guidelines specifically aimed at immune checkpoint antibodies. If you have questions or would like to talk more about how Charles River can support you, contact us at [email protected].