SMIP™ THERAPEUTICS
Trubion’s custom Small Modular ImmunoPharmaceutical (SMIP™) drug assembly technology was designed to specifically address the limitations of monoclonal antibodies (mAbs). SMIP therapeutics, which have been clinically validated, are single chain polypeptides comprising a binding domain, a hinge domain and an effector domain designed in an effort to meet predetermined therapeutic criteria for specific diseases. SMIP proteins are mono-specific therapeutics — a drug that recognizes and attaches to a single antigen target and initiates biological activity. SMIP therapeutics have unique structural design characteristics and are significantly smaller than whole antibodies, which allows for better in vivo penetration.
SMIP technology enables us to design and develop differentiated product candidates for a range of targets and biological activities that have the following advantages:
Unique Structural Characteristics: When engaging cell surface targets, SMIP proteins are capable of co-approximating cell surface molecules in unique ways. The binding domains of SMIP product candidates have a different geometry than the binding domains of conventional mAbs – that is, the binding domains are closer together. The structural format of SMIP proteins permits engineering a range of distances between the binding domains. SMIP proteins are also capable of binding and neutralizing soluble molecules, if so desired.
Differentiated Product Candidates: SMIP product candidates can be engineered to deliver the desired cellular signaling responses. These unique properties can be used to generate biological responses not observed with mAbs. In addition, SMIP proteins can be engineered to balance target signal induction, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mediated activity. The ability to customize this balance of biological activities can result in safer and more effective immunopharmaceuticals.
Improved Biodistribution. SMIP product candidates have a particle size that is approximately one-half the size of mAbs. Smaller molecules have been demonstrated to penetrate tissues more readily, a feature we believe will provide increased therapeutic benefits.
Reliable Manufacturing. SMIP product candidates can be produced at large scale in mammalian cell expression systems from readily available materials.
Broad Therapeutic Application: SMIP product candidates have potential application in diabetes, solid organ transplant, oncology, and other high unmet need areas.
DRACO Anti-CD3 Program: Therpeutic Manipulation of the TCR Complex
Utilizing our proprietary SMIP™ format, Trubion has developed anti-CD3 product candidates that demonstrate significant benefits from other anti-CD3 directed monoclonal antibodies. CD3 is a component of the T-cell receptor complex and has been targeted for therapeutic development (e.g., OKT3) with limited success. Second generation anti-CD3 monoclonal antibodies (mAbs) are currently in development. The second generation anti-CD3 mAbs have a modified human IgG Fc domain to decrease FcR interactions. These product candidates are currently in clinical testing in AIID indications (e.g., diabetes) and have demonstrated positive clinical responses but the safety profile still needs improvement. Patients treated with some of the second generation monoclonal antibodies continue to demonstrate cytokine release syndrome (CRS) (Sandborn, et al.DDW 2007; Woo,etal , DDW 2006). Trubion has developed SMIP product candidates that retain immunosuppressive activity while demonstrating significant reductions in cytokine release activity.
DRACO Program Overview
Structural Characteristics of the SMIP format lead to a novel signaling profile: When engaging cell surface targets, SMIP therapeutics are capable of co-approximating cell surface molecules (such as CD3) in unique ways. SMIP product candidates have a differentiated geometry of the binding domains in comparison to conventional monoclonal antibodies. The proximity of the binding domains in SMIP proteins can be engineered to provide a range of distances between the binding domains and thus generate a range of signaling responses.
Trubion has developed unique insight into the causes of CRS in vivo: Utilizing surrogate molecules, Trubion has demonstrated that other mutations, in addition to Fc:FcR interactions, can lead to decreased cytokine release in vivo. Surrogate SMIP molecules do not induce CRS but retain biologic potency in mouse models. These observations are available for generating an optimized SMIP product candidate.
Humanized SMIP product candidate identified: The SMIP product candidate demonstrates minimal cytokine release in vitro but demonstrates high inhibitory activity in a human mixed lymphocyte reaction (MLR) assay. This molecule binds to NHP T cells and is available for testing in mouse (Hu-SCID) models of CRS.
SMIP™ Product Candidates: Design and Assembly
Each of our SMIP product candidates contains a binding domain, a hinge domain and an effector domain. Our custom drug assembly technology permits us to engineer desired characteristics into each domain. This means that Trubion scientists can design and develop novel product candidates for a range of targets, as well as a range of differentiated product candidates for a particular target.
SMIP product candidates are specifically designed to meet predetermined therapeutic specifications for biological activity and binding activity based on our biological assessment of the validated target in the proposed disease indication. Biological activity and binding activity are the two most important characteristics of a protein immunotherapeutic. The diagram below is a representation of the steps in our assembly process.
Highlights
