MABTOX

"Generation and Evaluation of ""Next-generation"" Antibody-Toxin-Conjugates for Cancer Therapy"

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 Obiettivo del progetto (Objective)

'Therapeutic antibodies have transformed cancer therapy during the last decade, due to their high selectivity of targeting cancer cells in comparison to standard small molecule chemotherapy. Most recently, the coupling of cellular toxins to therapeutic antibodies has demonstrated an even greater efficacy in the therapy of cancer and the first, highly potent antibody drug conjugate (ADC), Adcetris®, was FDA approved in August 2011. All ADCs currently in clinical development are generated by chemical conjugation of small molecule toxins to antibodies. This is an inefficient process, as site and ratio of toxin coupling cannot be controlled. In addition, the chemical conjugation involves chemical modification of potentially functional parts of the antibody. This can have negative effects on stability, specificity, CMC properties and the overall structure of the antibody. All this renders ADC manufacturing highly challenging, complicates regulatory procedures, and adds to development time and costs. The SME consortium has complementary proprietary technologies and proposes to leverage this complementary expertise and know-how for defining novel processes of enzymatically conjugating small molecule toxins to antibodies that allow full control about toxin coupling site and ratio. Due to the high selectivity of enzymatic conjugation and physiologic conjugation conditions, it is expected that more homogeneous ADCs are generated with better CMC properties, higher potency, and at lower cost-of-goods in manufacturing. The consortium members believe that this represents a disruptive technology that will be highly competitive to traditional chemical conjugation, currently dominated by U.S.-based ADC technology companies Seattle Genetics and Immunogen. In addition to novel composition-of-matter IP, important novel know-how for ADC development will be created. Most importantly, better quality and potency of these “next-generation” ADCs will eventually benefit cancer patients.'

Introduzione (Teaser)

A European consortium is combining expertise to develop new technologies for the synthesis of improved antibody drug conjugates.

Descrizione progetto (Article)

Therapeutic antibodies against specific cancer antigens have transformed cancer therapy during the last decade. They exhibit high selectivity and fewer side-effects compared to standard small-molecule chemotherapy drugs. Recently, antibodies have been conjugated to cellular toxins, demonstrating even greater efficacy for the therapy of certain cancers. The first two antibody drug conjugates (ADCs) have been approved by the United States Food and Drug Administration (FDA) to treat Hodgkin's lymphoma and therapy-resistant HER-2+ breast cancer.

Traditionally, ADCs are generated by chemical coupling of small-molecular-weight toxins to free lysine or cysteine residues of the antibodies. However, this process cannot be controlled and results in a largely heterogeneous pool of ADCs of varying structure and efficacy. In addition, during chemical conjugation the 3D structure of antibodies, and hence their function, could be irreversibly damaged.

The scope of the EU-funded project 'Generation and evaluation of "next-generation" antibody-toxin-conjugates for cancer therapy' (http://www.mabtox.org/ (MABTOX)) is to develop novel enzymatic methods for the site-specific and controlled conjugation of toxins to ADCs. For this purpose, it has brought together small and medium-sized enterprises with expertise in antibody engineering, enzymatic conjugation and medicinal chemistry.

During the first part of the project scientists have successfully produced modified toxins and antibodies against known cancer targets. These recombinant molecules carry motifs that will serve as sites for enzymatic conjugation using two types of transpeptidases, the so-called intein and sortase enzymes. After successful generation of all components required for these novel enzymatic antibody conjugation methods, the consortium is ready to test this technology to produce next-generation ADCs.

It is now well established that better defined and homogeneous drugs are needed to enhance the safety, predictability and efficacy of ADCs for treating cancer patients and to obtain regulatory approval. MABTOX project partners hope to make this a reality through an enzymatic method that can deliver homogeneous ADCs with improved properties in comparison to their chemically conjugated counterparts.