HuCAL^®

MorphoSys’s HuCAL^® (Human Combinatorial Antibody Library) technology is a unique and innovative concept for the in vitro generation of highly specific and fully human antibodies.

The collection of several billion distinct, fully human antibodies allows for the rapid selection of antibodies with high affinity and specificity. The recombinant antibody technology of HuCAL^® enables the generation of therapeutic and diagnostic antibodies, including those binding to difficult antigens.

HuCAL^® antibodies are produced in bacteria, and the technology enables in vitro selection to isolate antibodies with the desired characteristics. HuCAL^® is generated by de novo gene synthesis, and the large library is screened with a technique called phage display to identify the antibody with a high affinity to the investigated antigen.

95% of the structural diversity of the human antibody repertoire consists of seven heavy chain and seven light chain variable region genes. The combination of these genes gives rise to 49 frameworks in the HuCAL^® master library displaying several billion distinct fully human antibodies.

Further fine-tuning of the antibodies is possible due to MorphoSys’s proprietary TRIM technology that facilitates the targeted diversification of CDRs. Pre-assembled trinucleotides are used in the chemical synthesis of the CDR sequences, thereby ensuring complete control over amino acid composition while avoiding stop codons. TRIM allows synthesizing any combination of amino acids at each single position of the variable region in a ratio reflecting exactly the one found in humans. As a result, these CDR libraries are of substantially higher quality than those developed using more conventional approaches.

Ylanthia^®

which is the industry’s largest antibody Fab library to date, uses a unique concept for the in vitro generation of highly specific and fully human antibodies.

Ylanthia^® goes one step further than all current antibody technologies. The technologies currently available make the successful development of therapeutic antibodies difficult in two respects. On the one hand, many antibody programs fail in later development due to inadequate biophysical properties, which classify the active ingredient as "undevelopable". If an antibody cannot be produced on a larger scale or if other properties adversely affect its handling, the chances of successful commercialization decrease. On the other hand, earlier generations of technology fail to deliver antibodies against all possible targets (epitopes) of disease-relevant target molecules. This can lead to highly promising target molecules being wrongly rejected. A lack of structural diversity, i.e. diversity, in the generation of antibodies means that not all possibilities to bind to a promising target molecule are exhausted and its role in the course of the disease is underestimated. The Ylanthia^® technology has been specifically designed to remove these hurdles.

The antibody library has all the necessary prerequisites for selecting antibodies against all possible starting points of disease-relevant target molecules due to the structural range and diversity of the library. If one can succeed in exhausting all of the possibilities for binding promising target molecules, this can result in unique product opportunities and compound candidates that can intervene at the crucial points in a disease process.

Ylanthia^® takes antibody technology beyond current methods. A guiding principle underlying the design and construction of the Ylanthia^® library was to ensure that the library is of the highest possible quality. Features which distinguish Ylanthia^® from other technologies include:

• Size and heavy/light chain pairing: Ylanthia^® is the industry’s largest known antibody Fab library, comprising over 100 billion distinct, fully human antibodies. Ylanthia^® uses 36 fixed, naturally-occurring heavy and light chain framework combinations, which translates into unprecedented structural diversity. Great care was invested into the antigen binding site design. The library’s diversity is expected to result in antibodies against previously inaccessible target molecules and unique epitope coverage.
• Biophysical properties: Antibody frameworks were pre-selected for expression levels, stability and aggregation behavior. A shift towards higher stability and stress tolerance will increase shelf life and serum stability of resulting antibody-products, making them more cost-effective to produce and administer. A higher solubility in turn opens up the path for more convenient formulations for patients, such as subcutaneous administration.
• Optimization: When needed, antibodies from the Ylanthia^® library are optimized using MorphoSys’s proprietary Slonomics^® technology, which MorphoSys obtained through its acquisition of Sloning BioTechnology in 2010. Ylanthia^® thereby distinguishes itself in a central respect from HuCAL^®, which relies on a modular gene design and pre-formed cassettes for antibody optimization. Slonomics^® enables optimization of Ylanthia^® antibodies with unprecedented speed and flexibility.

Slonomics^®

is a proprietary fully automated genetic-engineering platform that utilizes sets of double stranded DNA triplets in the controlled fabrication of highly diverse combinatorial gene libraries.

The superior combinatorial library enables researchers to increase the success rate of their screening for new and optimized therapeutic antibodies, proteins or industrial enzymes.
Applied to antibodies, Slonomics^® becomes arYla^® - a platform providing high quality, ratio-controlled, combinatorial libraries for optimizing antibodies on their functional-, expression- or biophysical properties.