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FIT-Ig (Fabs-In-Tandem)

Antibodies were designed by nature to bind particles they recognize as potentially harmful thereby flagging them for the immune system. Antibodies share a common general Y-shaped structure. While the stem of the Y, the Fc-domain, remains constant among antibodies of a given species, the two arms, the Fab-domains, constitute the antigen binding part that varies from antibody to antibody. The Fab-domains of a given antibody molecule are identical and are directed against one defined target molecule, called an antigen.

Bi-specific antibodies are engineered from two different monoclonal antibodies combining their key features into one molecule. They provide new options for the treatment of many fatal diseases such as cancer. However, even minor modifications to an antibody can significantly alter its binding properties, pharmacokinetics, stability, solubility or the ability to manufacture the molecule in sufficient amounts. Most commercially available bi-specific technologies rely on significant modifications of the basic structural elements of an antibody. The vast majority of them insert mutations to the Fc-domain or omit it entirely, many of them add fragments such as less stable single chain fragments (scFv’s) or linkers that can completely change the overall stability or enhance immunogenicity.

EpimAb’s FIT-Ig (Fabs-In-Tandem) technology utilizes a novel and efficient approach for generating bi-specific antibodies (see figure below). By re-arranging the DNA sequences of two monoclonal antibodies into three constructs (#1, #2, and #3 below) and co-expressing them in mammalian cells, EpimAb generates bi-specific FIT-Igs that fully retain the biological function of their parental monoclonal antibodies. No Fc mutation is required; no scFv elements are used; no linker or peptide connector is needed. The Fab-domains in each arm work “in tandem” forming a tetravalent bi-specific antibody with four active and independent antigen binding sites.

With the FIT-Ig molecules generated to date, EpimAb demonstrated that the three fragments, when expressed together in a single mammalian cell, assemble properly to form a FIT-Ig in the correct structural orientation. These molecules have been characterized and demonstrated properties of conventional therapeutic monoclonal antibodies.

This includes: • expression in good quantities and easy one-step purification; • binding to their antigens with the affinity of their parental antibodies; • demonstrating comparable stability and solubility to monoclonal antibodies in standard buffer systems; and • a pharmacokinetic profile evaluated in vivo that is comparable to monoclonal antibodies after intravenous or subcutaneous administration. The FIT-Igs that are currently being investigated at EpimAb were selected based on the scientific rationale to combine the two functions of the parental antibodies into one single molecule. These bi-specific molecules are of particular interest to scientists and clinicians in the area of immunology, oncology, immuno-oncology and orphan diseases. By increasing the variety of FIT-Ig molecules further, EpimAb plans to build up technical know-how and generate additional scientific insights to explore the unique features and overall capabilities of this new drug format.