Engineering

Generate variant designs and build new antibodies based on these designs. Optimized leads have improved developability critical for downstream processing and manufacturing.

This tool is useful for engineering antibodies to improve their developability. The tool lists desired mutations entered via the Liabilities or PFA, or directly in the Engineering tool. The tool can be used to generate combinatorial variant designs and build new antibodies based on these designs.

Using the Engineering tool exemplifies the core work principle to "Be Inherently Lazy"—working very hard to build an easy, reproducible, and error-eliminating method to do work. Rather than copying a parent sequence in Excel multiple times and editing mutations in the copied versions by hand to generate combinatorial variants (which is slow, repetitive, and prone to human error), you can use the Engineering tool to design, filter, and build complex combinations in a fraction of the time with absolute consistency.

Accessing the Tool

Select exactly one antibody in the Project View. Go to the Edit menu and select Engineering. This will open the Engineering workspace in a new tab.

Engineering Mutation Designs: Engineering Variant Designs:

Using the Tool

• Mutation Sets: Mutations are grouped into Sets, allowing you to manage parallel design paths (e.g., one set for humanization, another for liability removal) on the same antibody without overlapping configurations.
  • The Default set is the standard workspace and cannot be deleted. The tool always opens to this set by default.
  • Use the ⋮ menu next to the set dropdown to create a New Set Name or delete the current set.
  • Mutations from any set will show as an indicator dot in other tools, but only the Default set mutation will show in the Engineering modal in those tools.
• Edit Menu: Select mutations in the grid to enable the Edit dropdown menu in the toolbar. From here, you can Edit Mutation (if only one is selected), Delete selected mutations, or use Move to Set to transfer the selected mutations from your current set into another set.
• Mutation Designs: Click a residue in the Sequence tab, or in a tool supporting Engineering such as Alignment, PFA, or Liabilities, to open a mutation design. Mutation designs may be edited. The parental residue may be included in the variant design set or not. A parental residue is usually included if the user suspects the position may be necessary for function, in which case mutating the site would be risky.
• Observations: Click a residue to enter an observation for that IMGT position. These are displayed in the Observations tab and on a clicked residue.
• Min & Max Mutations Filters: Directly above the toolbar, you can specify Min Mutations and Max Mutations limits (defaulting to NA). The dropdown options populate dynamically based on the number of checked mutational designs in your grid. For example, if you check 16 mutation designs and set Min to 3 and Max to 5, only combinatorial variants carrying exactly 3, 4, or 5 mutations relative to the parental sequence will be generated.
  • The dynamic combination counter below the toolbar (e.g., 16 selected, 6,748 combos) automatically recalculates in real-time to show the exact number of combinations that satisfy these criteria.
• Generate Variant Designs: First, use the Set dropdown to ensure you are viewing the correct set of mutations. Then, use the Generate dropdown menu in the toolbar to build combinations from that active set. The variant designs may be generated with parental residues as defined in the mutation designs using "Generate Combinations", or all parental residues ignored using "Generate Combinations (Non-Parent)". Only variants matching your active Min/Max filters will be generated.
• Variant Designs: The generated designs are displayed in the Variant Designs tab. Designs may be deleted or selected for building new antibodies.
• Build FASTA: Selected variant designs may be used to build and download a FASTA file.
• Build Selected: Selected variant designs may be used to build new antibodies. New antibodies are added to the project and the parent antibody is assigned.

Using Sets - An Example

1. Select Humanization on a parent entry.
2. Select the Sapiens "Suggest Mutations" and click "Apply Mutations".
3. From the main grid select Engineering for the parent entry.
4. In the upper right in Mutation Designs select the vertical dots menu, New Set Name, enter "Humanization - Sapiens", and click Save.
5. Select the mutations in the grid and select Edit > Move to Set > Humanization - Sapiens.

You now have a set of mutations isolated as "Humanization - Sapiens". You could then return to the Humanization tool, perform a different humanization and save its mutations as its own set. You can build combinatorial variants by first selecting the desired set and mutants, and then using Generate.