Concortis has developed a core ADC technology platform that sets a new industry standard for ADCs and will transform biologics such as antibodies, proteins, and peptides into therapeutics that are more efficient. Using our ADC technology, G-MAB™ antibody library, proprietary toxins, and K-Lock™ and C-Lock™ conjugation methods, we create a comprehensive technology platform that supports our scientific research, focusing on ADCs for targeted cancer therapy.
G-MAB ANTIBODY LIBRARY
Our parent company, Sorrento Therapeutics, Inc. (NASDAQ: SRNE) has developed G-MAB technology, one of the largest and most diverse fully human antibody libraries in the industry. This antibody library platform was designed to facilitate the rapid identification and selection of highly specific monoclonal antibody (mAb) therapeutic product candidates.
Sorrento’s library achieves its high diversity from a large collection of high-quality antibodies. The theoretical diversity of our library has been calculated to be more than ten quadrillion (10E16) unique antibodies, making it one of the largest fully human antibody library available to pharmaceutical and biotechnology companies for drug discovery and development partnerships. Exemplary of the uniqueness of the library quality are Sorrento’s immunomodulatory anti-PD1 and anti-PD-L1 mAbs, which are, to the company’s knowledge, the only mAbs targeting PD-1 and PD-L1 in development derived from an antibody library. Sorrento has established a comprehensive program aimed at the discovery and development of immunomodulatory antibodies for the treatment of cancer and potentially other disease indications.
Furthermore, the library has also yielded mAbs that target G-protein-coupled receptors (GPCRs), which are important drug targets but have historically been difficult to target using monoclonal antibodies.
Preclinical models demonstrated that Sorrento’s GPCR antibodies have excellent properties resulting in significant reduction in the disease score when evaluated in a mouse model of multiple sclerosis.
Sorrento has advanced over 10 preclinical monoclonal antibody development candidates in the G-MAB pipeline, including those aimed at treatments for oncology and inflammation.
We have developed a panel of proprietary toxins derived from natural cytotoxic compounds with our in-house chemical design and synthesis to optimize performance of our payloads. Various structural modifications of known compounds were implemented through our in-house chemical design and synthesis to address issues such as efficacy, toxicity, conjugation and stability.
These toxins have been screened on multiple tumor cell lines and through in vivo studies.Our selection of toxins provides a spectrum of different mode of actions including tubulin inhibitors, RNA polymerase inhibitors, and DNA damaging agents.
The therapeutic potential of many ADCs that are currently in pre-clinical or clinical development, including FDA-approved ado-trastuzumab emtansine (Kadcyla®) suffered from very narrow therapeutic window. There is constant need in the ADC field for further improvement.
Many ADCs that are currently in pre-clinical or clinical development including FDA approved ado-trastuzumab emtansine (Kadcyla®), have very narrow therapeutic window and further improvements may be required to enhance the therapeutic potential. Many of those ADCs were produced by random conjugation to the surface lysines on an antibody to yield heterogeneous mixture that is very difficult to characterize and ensure batch to batch consistency. Site-specific conjugation has recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Herein, we developed a proprietary K-Lock™ conjugation method that is a linker-controlled, site-selective conjugation technology targeting 2 native Lys sites out of 80-90 Lys present in an antibody WITHOUT the need of antibody modification for cell engineering or enzymatic modification steps that are used in various site-specific conjugation strategies use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycosyltransferases and transglutaminases. The generated ADCs have fewer regioisomers and lower DAR while maintaining comparable potency to ADCs generated from standard conjugation methods.
FDA-approved ADC, brentuximab vedotin (Adcetris®), is produced through reduction of four inter-chain disulfide bonds followed by partial maleimide conjugation to the exposed sulfhydryl groups. ADCs generated with this approach are polydisperse and the drug-antibody ratios (DAR) ranges from 0–8.
Our proprietary C-Lock™ conjugation method utilizes novel linker chemistry to reconnect the antibody heavy and light chains following the reduction of the inter-chain disulfide bonds. The crosslinking introduces one payload per reduced disulfide bond. The resultant ADCs possess enhanced stability in vitro and in vivo, with a probable improvement in PK and PD profile. The cross linking conjugation process can be optimized to consistently produce an ADC with DAR 4 in very high yield, thereby simplifying the purification and characterization process in ADC production.