iADCs and Antibody-Drug Conjugates
Sutro’s cell-free expression technology provides a rapid and powerful platform for the discovery and development of next generation antibody-drug conjugates (ADCs).
What we Do
Next Generation Cancer Therapeutics
We have also expanded our ADC technology platform to include tumor targeting immunostimulant ADCs, or iADCs.
Our XpressCF+® Platform has enabled a breakthrough technology to engineer a homogeneous iADC molecule dually conjugated with an immunostimulant and a cytotoxic warhead. Our novel iADC design is intended to deliver two different drugs directly to the tumor, and not only kill tumor cells but also locally prime an immune response to the patient’s particular tumor cells. We believe that our iADC approach creates a new therapeutic opportunity by combining the best features of an ADC with the biology of a personalized vaccine.
Advantages of our ADC Platform
Current ADCs in clinical development have immense promise, but many of them are limited by the fact that they are structurally heterogeneous populations in which the position and number of conjugated linkers and warheads vary significantly. Such heterogeneity prevents the definition of structure-activity relationships (SARs). Consequently, using traditional ADC technologies prevents researchers from discovering and developing candidates with optimal therapeutic indices and can result in products with unpredictable and sub-optimal pharmacokinetic properties, stability and efficacy.
Sutro can precisely incorporate non-natural amino acids (nnAA) at nearly any site in an antibody structure, thereby allowing for single-species ADCs with site-specific conjugation of linker and warhead. Of vital importance in this process is Sutro’s ability to perform rapid and parallel synthesis of numerous variants taking advantage of a substantial number of different sites, enabling analyses early in discovery to define SARs and locate the best positions for nnAA incorporation based on:
- Site-Specific ADC Technology
- Antibody expression
- Efficiency of incorporation of the nnAA
- Optimized Linker/Warhead
- Linked/warhead conjugation efficiency
- Stable linker warhead while circulating in patients
- Therapeutic Index/Safety
- Cell killing efficiency
- Target bidding efficiency
- Internalization Characteristics
The cell-killing effects of ADCs depend on both the location of the warhead and the drug to antibody ratio. Sutro can control both of these variables with exquisite specificity, resulting in truly optimized product candidates. To address the challenge of manufacturing nnAA-containing ADCs, Sutro has engineered additional versions of cell-free extract that achieve high rates of incorporation of nnAAs and developed chemistries that allow for efficient and stable conjugation of linker/warheads to antibodies.
Bispecific and Engineered Antibodies
Sutro’s cell-free expression technology provides a rapid and powerful platform for the discovery and development of antibodies that bind simultaneously to two separate antigens (bispecific antibodies). Our collaboration with Merck KGaA, Darmstadt, Germany (also known as EMD Serono in the US) exemplifies our bispecific technology approach.
Bispecific antibodies can be designed to achieve different purposes:
- To bring an antigen-expressing cell in close proximity to a killing cell
- To increase the apparent affinity of binding to an antigen using avidity
- To increase the relative selectivity of binding of an antibody to a particular antigen on diseased tissue over normal tissue by using a similar avidity approach, to bind two antigens expressed on the same diseased cell
- To increase the internalization rates of particular antigens on a cell’s surface by cross-linking two different cell surface proteins or by binding to two different epitopes on the same protein.
While many different bispecific antibody formats have been exemplified using cell-based expression systems, and some have been successful enough to show promise as new therapeutics, the precise geometry and spatial orientation of binding domains, linkers and functional domains can be a challenge to optimize.
Additionally, the use of cell-based systems has revealed immense difficulties in expressing bispecific antibodies, particularly at larger scale, often resulting in poorly folded and aggregated material. Consequently, using traditional cell-based technologies prevents researchers from discovering and developing bispecific candidates with optimal therapeutic indices and can result in products with unpredictable pharmacokinetic properties, stability and efficacy.
Sutro’s technology has the ability to perform rapid expression and characterization of many variants early in discovery to define structure-activity relationships and thereby optimize:
- Binding efficiency to each target
- Spatial orientation and linker design
- Protein expression and folding efficiency
Sutro can rapidly screen candidates to identify molecules with the best overall combination of these properties resulting in optimized product candidates.
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