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Application Biopharma Antibody Engineering

Antibody discovery, optimization, and engineering

The Problem

How do you make and test all of your candidates?

The Tierra Solution

Tierra produces hundreds of discrete proteins at a time in as little as three weeks, to deliver your antibody precursor candidates with superior binding affinity and specificity.

Antibody discovery, optimization, and engineering is limited by the ability to produce diverse antibody modalities at high-throughput and scale. What if, instead of having to down-select from a phage display library with inherent biases or a computationally predicted library, you could make and test all candidates? Tierra enables production at hundreds at a time in three weeks or less, to get you to your antibody precursor with superior binding affinity and specificity.

Single Domain Formats: Nanobodies/VHH, scFvs, BiTE

Single-domain formats such as nanobodies, scFvs, and BiTEs can be easily submitted for evaluation and production using Tierra’s web interface. Tierra’s biologics-optimized cell-free system can stabilize the multiple intra-disulfide bridges present in these formats. In addition, repeat regions in bispecifics and trispecifics can be easily and quickly assembled and expressed in Tierra’s systems, avoiding cloning issues commonly seen with cellular expression. These antibody precursors can be delivered either tag-free by default or with common affinity tags needed for downstream characterization.

Multi-Domain Formats: Fab, TCR, mAb

Multi-domain formats are accessible using Tierra’s custom platform with Tierra scientist support. These formats can be particularly challenging to produce and optimize in high-throughput in HeLa or CHO cell lines. However, the Tierra platform provides multiple advantages over cellular methods, including:

  • Individual optimization of domains. Different domains may have different properties. For example, while light chains may be easy to produce individually, heavy chains may require co-expression or solubility optimization for stability. In one or two high-throughput experiments, Tierra scientists can rapidly optimize individual domains across tags, conditions, and other impacting variables.
  • Disulfide bridge formation and optimization. Multi-domain formats contain multiple inter-and intra-cellular disulfide bridges that need successfully formed to produce the final Fab, TCR, or mAb. Tierra’s unique biologics-optimized cell-free system stabilizes these disulfide bridges and supplements cofactors needed for successful antibody production. This allows access to chemistries typically reserved for eukaryotic cell lines.
  • Stoichiometry and yield optimization. Once successfully produced, the multi-domain Fab, TCR, or mAb can be easily optimized for yield at the sequence-level or at the domain-level. As cell-free systems are open, changing properties involves quickly changing the concentration of DNA provided, eliminating the need for complex cellular engineering of regulatory regions and of cloning new variants and designs.

As a proof-of-concept Tierra has produced a 16 disulfide-bridged, full-length purified trastuzumab mAb, which has been validated for binding to its HER2 target. Once your model Fab, TCR, or mAb is validated, further designs can be quickly iterated against and tested for specificity.

R: Antibody ProL-HRP (k light chain) SDS-PAGE of purified trastuzumab heavy chain and light chain. 173 kDA by CE-SDS-PAGE

ELISA measuring biding to human HER2 protein. Dilution series of Tierra-made trastuzumab shown in comparison to 4-parameter logistic regression (4PL) fit to signal from five trastuzumab concentration standards. Signal from phosphate-buffered saline (PBS) is shown as reference.

Contact us to advance your antibody discovery, optimization, and engineering efforts using the power of cell-free biology.

Protein synthesis can be easy, fast, and reliable.

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