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Antibody Engineering Capability


Antibody Engineering Capability

Protein Engineering
Directed Evolution
Affinity Maturation
Structure-Based Protein Design

Protein Engineering

Harbour Mice® transgenic mice platforms (H2L2 and HCAb) enable the generation of fully human antibodies with excellent developability for therapeutic applications. Additionally,  in certain scenarios, protein engineering is required to modify molecules to acquire new properties or create innovative modalities.

Our scientific team has accumulated extensive experience in protein engineering and commits to use state-of-the-art techniques to deliver the best biologics. We leverage powerful surface display technologies to capture millions of molecular variants and employ structural biology and molecular dynamics to capture atomic changes.

Antibody Discovery in a “Single Day” by Beacon® Technology

Berkeley Lights Beacon® Optofluidic System

Beacon® can support the separation and screening of 10,000+ cells in a single run with one 14K or 20K OptoSelect chip. Enriched plasma cells are individually loaded into NanoPen chambers on the chip. Our proprietary medium preserves the viability and facilitates antibody secretion of these plasma cells. Multiple in-chip assays can be sequentially performed to screen those plasma cells, and the cells with desired signals wll beare selected and exported one by one through OEP technology. The entire workflow is completed in just one day.

High Throughput Chip

Each 20K OptoSelect chip has 20,000 individual NanoPen chambers and can separate and screen up to 20,000 cells within a single run.

Versatile In-Chip Assays

With real-time fluorescent microscopy technology, different assays could be performed in-chip for plasma cell screening, including:

  • Antigen beads binding assay
  • Cell binding assay
  • Competition assay
  • Reporter cell assay

All these advantages make SBC platform to become highly efficient and robust antibody discovery platform.

Precisely Single Cell Exporting

Opto-electro positioning (OEP) technology precisely manipulates and unloads cells to 96-well plates preloaded with single-cell sequencing reagents.

Directed Evolution

We have established both phage display and yeast display technology platforms to meet various applications of directed evolution for protein engineering. These platforms facilitate the discovery of antibodies from immunized animals, human PBMCs or other sources , and facilitate tasks such as affinity maturation, PTM removal, cross-reactivity optimization, and improvement of biophysical properties.

Both phage display and yeast display technologies are suitable for multiple different applications, however, each technology has its own advantages in specific scenarios. Our scientific team selects the most suitable technology based on the nature of the molecule.

Affinity Maturation

Affinity maturation stands as a crucial and widely employed application of surface display technologies in the field of antibody engineering. By combining yeast display technology with streamlined processes for FACS sorting and antibody screening, the workflow of affinity maturation has been significantly shortened, enabling the rapid generation of candidates with enhanced binding activities.

The figure below illustrates the workflow for improving the binding affinity of an HCAb molecule using the yeast display technology platform. Using an anti-PD-1 HCAb as an example,the monomeric VH domain with proper tags (e.g., His-tag) was displayed on the yeast cell surface. Mutagenic libraries were created for each CDR region using degenerated primers, which covered the potential antigen binding sites within the three CDRs. These libraries were subject to MACS sorting and sequential multiple rounds of FACS sorting by proper forms of antigens to isolate the population of yeast cells with increased binding activities. After analyzing the VH sequences of the variants from different mutagenic libraries, the “hotspot” mutations which make critical impacts on antigen binding were identified. The binding activities of the variants from each CDR mutagenic library can be ranked by FACS or Octet. The “hotspot” mutations from each CDR were then combined into a new mutagenic library to include the combinatorial mutagenesis across different CDRs. The new library was subjected to new round of FACS sorting and screening, and the new variants carrying multiple mutations with significantly increased binding activities can be retrieved.

As depicted in the figures below, VH mutants derived from Anti-PD1 parental HCAb exhibit much stronger binding activities to human PD-1 on CHO-K1 cells. Consequently, these mutants also demonstrated significantly improved activities to inhibit PD-1/PD-L1 signaling in the reporter gene assay.

Structure-Based Protein Design

With our expertise in structural and computational biology, we have the capability to design and optimize novel antibodies and other protein modalities to possess required properties such as excellent binding affinity, solubility or stability. This approach offers a faster and more cost-efficient way to generate superior biologics.

In the example below, our scientists developed a generalized approach to create “super-stable” HCAb. By introducing an additional intra-domain disulfide bond into the buried core of beta-sheets in the VH domain, a significant improvement in the thermal stability (Tm) of the antibody was achieved while other properties are kept unchanged. One of the designed variants, with the additional disulfide bond, exhibited a Tm of the VH domain-only format reaching nearly 75°C, demonstrating exceptional heat resistance.

AI-Guided Screening for Hyper Sequence Space

Enabling next-generation therapeutic innovation

We are building a new paradigm of antibody discovery by taking advantage of artificial intelligence and high throughput screening technologies. hyperSCREEN is a newly developed novel platform to leverage next-generation sequencing and machine learning to screen millions of sequences and enables us to identify rare sequences that are usually missed by conventional screening methods.

In one example, a panel of HCAbs specific to a novel target were identified by Beacon SBC that showed good bind activities to target cells. In parallel, another panel of HCAbs with good binding activities were identified by hyperSCREEN. Sequence analysis for the HCAbs from the two platforms showed good sequence diversity: 10 HCAbs from the two platforms were categorized into 3 clusters; each platform discovered a unique cluster containing multiple sequences, while both platforms also discovered similar overlapping sequences belonging to the same cluster. This example demonstrates the power of combining high throughput screening and artificial intelligence in antibody discovery.

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