A new proprietary coupling technology to generate homogenous Antibody-Drug Conjugates (ADCs)
Progresses in genetic engineering and immunology have paved the way for new types of monoclonal antibodies, at the first rank of which are Antibody-drug conjugates (ADCs). ADCs are able to bring cytotoxic molecules (toxins) within the cancer cells by using antibodies as a carrier see the antibodies
Innate Pharma’s innovative coupling technology uses bacterial transglutaminase (BTG) enzyme. It aims to address the heterogeneity of the coupling between the antibody and the drug of interest, heterogeneity that affects the therapeutic efficacy of antibody conjugates. With this technology, a single point mutation in the antibody’s heavy chain generates either two or four enzyme-recognition sites, and linkers have been optimized to couple quantitatively at these positions.
The process results in homogeneous ADCs with a drug-to-antibody ratio of exactly 2:1 or 4:1 in a robust and time-efficient manner. The coupling is site-specific with minimal antibody scaffold modification, therefore only adding two steps in an already well-established manufacturing procedure widely accepted by regulators.
Innate’s technology helps to generate homogeneous ADCs in 2 steps with an exact antibody / toxin ratio
Moreover, Innate Pharma’s new BTG-based process requires a minimal amount of toxin, which can be a crucial argument with regard to large-scale production of ADCs. This technology displays high versatility appropriate for testing various linkers and toxins such as PBD(1), in high-throughput screening. Indeed, this chemo-enzymatic approach not only allows conversion of virtually any IgG1 into a functional ADC, but also enables comparison of various antibodies, linker systems or toxin.
BTG-ADCs are stablein vivo, without DAR variation over 2 weeks, with a lower clearance compared to ADCETRIS®. In addition, quantitative time-dependent in vivo biodistribution studies show higher tumor uptake than ADCETRIS® and exhibit lower non-specific liver and spleen uptakes, resulting in higher (>3 fold) maximum tolerated dose and therefore an improved therapeutic index.
Innate Pharma’s technology could be used internally to expand its portfolio of developmental candidates or form strategic partnerships.
Innate Pharma has collaboration with ETH-Hönggerberg, Switzerland, on the development of this technology.
(1) Pyrrolobenzodiazepine dimers, a class of highly potent toxins.
Lhospice et al, 2015. Site-specific conjugation of monomethyl auristatin E to anti-CD30 antibodies improves their pharmacokinetics and therapeutic index in rodent models Mol Pharm. Panowski et al, 2014. Site-specific antibody drug conjugates for cancer therapy MAbs.