Overview of the Antibody Drug Discovery

Antibody drug discovery

Antibody Drug Discovery

Monoclonal antibodies

In 1975, British scientist Milstein and French scientist Kohler fused mouse B lymphocytes with tumor cells to form hybridoma cells. The first generation of monoclonal antibody (MAb) was born. This antibody has high specificity, uniform properties, and is easy to produce in large quantities, which brings new hope for the treatment of tumors and other diseases. However, the human immune system can recognize murine monoclonal antibodies, produce and neutralize human anti-mouse antibodies, which limits its application. In addition, due to the relatively large molecular weight of the antibody itself, the low blood vessel penetration in the body, and the high production cost, it is not conducive to large-scale industrial production. Therefore, it is urgent to find a new antibody drug with large-scale industrial production conditions.

Humanized antibody

Although chimeric antibodies can partially solve the problem of rejection of heterologous proteins, their murine variable regions may still induce HAMA responses and interfere with therapeutic effects. Therefore, the emergence of CDR grafted human antibodies has brought a turning point for the development of humanized antibody drugs. On the basis of chimeric antibody, CDR grafted antibody further uses human framework region (FR) instead of mouse origin, and only retains 3 murine CDRs, and the human origin can reach more than 90%. Studies have found that the supporting FR sometimes participates in antibody binding, reducing the affinity of antigen-antibody binding. Using affinity remodeling can maintain the specificity and affinity of the parent antibody to a great extent, solving the problem of antigen-antibody binding.

Fully human antibody

Through transgenic technology, fully functional fully human antibodies are processed in vitro, or genetically engineered antibody gene-deficient animals are used to express human antibodies, thereby obtaining fully human antibodies, avoiding the various shortcomings of murine monoclonal antibodies. Fully human antibodies are ideal antibodies for clinical treatment. Currently, fully human antibodies are mainly produced through methods such as antibody library technology and transgenic mouse technology.

What types of antibody drugs are there?

The first is conventional antibody drugs, that is, polyclonal antibody drugs. Since the discovery of diphtheria antitoxin in 1890 and the establishment of serum therapy, this type of antitoxin has been used, but its clinical application has been greatly affected by the inhomogeneity of the drug itself. limit.

With the development of technology, some new antibody drugs are also emerging. New antibody drugs have the same main structure characteristics as conventional antibody drugs, but there are more immunoconjugates and fusion protein markers, which increase the targeting and efficacy of antibody drugs.

Monoclonal antibody drugs include monoclonal antibody drugs for the treatment of tumors, anti-tumor monoclonal antibody conjugates and monoclonal antibodies for the treatment of other diseases. The targets of these drugs are mainly disease-related antigens or specific receptor molecules on the cell surface.

Genetically engineered antibody drugs refer to the general term for biopharmaceuticals prepared on the platform of high-tech biotechnology such as genetic engineering technology. Gene engineering (mostly using partial amino acid sequences of human antibodies to replace certain sequences of murine antibodies) is modified to prepare antibodies, thereby reducing the immunogenicity and function of murine antibodies.

Antibody drug discovery process

The following workflow shows an overview of the discovery process of therapeutic antibodies that led to the selection of clinical drug candidates.

1. Target Assessment & Validation

  • Gather evidence to support target selection rationale
  • Experimentally validate target
  • Establish project plan

2. Screening Preparation

  • Reagent generation for assay development and screening
  • Specificity, affinity, functionality testing
  • Evaluate non-cross- reactive antibody

3. Hit Generation & Lead Selection

  • Generate antibody hits using display and hybridoma technologies
  • Select lead molecules with favorable biochemical & biophysical properties
  • Demonstrate in vivo efficacy
  • Epitope mapping

4. Lead Optimization & Characterization

  • Antibody Production using transient expression or via stable cell lines for
  • Characterization
  • Humanization
  • Affinity Maturation
  • In vivo efficacy
  • Exploratory safety study
  • Biomarker development

5. Candidate Selection

  • Examine scientific data
  • Risk assessment
  • Safety assessment
  • Commercial viability assessment
  • Legal evaluation
  • Clinical plan
  • Regulatory plan
  • Manufacturing plan

Generally, screening, hit generation, and potential customer selection are also collectively referred to as "potential customer discovery." The activity leading to the selection of clinical candidates is called "preclinical" work/research. Although the language and choice of terms have changed from one publication to another, the concept remains the same.

* For Research Use Only.