SCORPION™ THERAPEUTICS
Trubion introduces a novel platform for the development of multi-specific protein therapeutics – SCORPION therapeutics. SCORPION therapeutics are single chain proteins comprised of an N-terminal binding domain, an effector domain based on immunoglobulin Fc regions, and a C-terminal binding domain, which are produced as disulfide-linked dimers by standard eukaryotic manufacturing cell lines. This proprietary molecular class leverages Trubion’s clinically proven SMIP™ (Small Modular ImmunoPharmaceutical) product format by combining single-chain binding and effector domain libraries, and adding additional C-terminal binding moieties. We utilize human protein sequences selected for stability, manufacturability, spatial optimization of the binding domains, and low immunogenicity.
Platform Overview: SCORPION Therapeutics
SCORPION therapeutics offer several important advantages:
Dual Targeting: unique structure enables simultaneous multi-valent engagement of two or more different soluble or cell-surface targets, providing the capability for differentiated signaling events
Desirable Pharmacodynamic Properties: retains immunoglobulin effector functions such as long in vivo half-life and Fc-dependent cellular cytotoxicity (FcDCC) activity, if desired
Rapid Development of Multiple Product Candidates: provides for a multitude of product candidates by utilizing binding domains in a variety of target combinations
Reliable Manufacturing: stable, homogeneous products with a robust manufacturing profile
Broad Therapeutic Application: autoimmune and inflammatory diseases (AIID), transplant, oncology, and other high unmet need areas
Click on the following for additional information on the SCORPION platform:
Beyond Abs Presentation – Sept 2009
TRBN SCORPION 2009 AACR Press Release
TRBN SCORPION 2009 AACR Poster
Trubion’s X1 SCORPION therapeutics are a family of molecules combining an inhibitor of TNF with selected single chain moieties to address the deficiencies of current therapies. TNF is a proven, well-established target in autoimmune and inflammatory disorder (AIID) indications, but there is still a significant unmet medical need for patients with such diseases who fail to respond (25-40%) or fail to sustain a long term response (20%) with existing TNF therapies. In addition, differentiated product candidates are likely to be important since the field is becoming increasingly competitive. Biologic therapies that target more than one cytokine (e.g., ustekinumab) have demonstrated superiority to Enbrel® in some therapeutic settings (e.g., psoriasis). Combination therapy using bivalent molecules that simultaneously target TNF and other inflammation targets of interest may better address patient needs and the commercial marketplace.
Program Rationale: TNFR X Anti-IL-6/IL-6R – X1 SCORPIONTM Therapeutic
Inhibition of IL-6 (via anti-IL-6R, e.g. Actemra®) has previously demonstrated benefit in patients with rheumatoid arthritis, even those who are refractory to α-TNF-based therapy. Thus, combinatorial inhibition of TNF and IL-6 may be more effective than either single agent alone.
Trubion has developed an array of IL-6 inhibitors that we believe will expand the activity of TNF-based therapies when used in conjunction with our SCORPION technology. Importantly, some of the available binding domains specifically inhibit only a portion of the IL-6 signaling process (targeting trans-signaling induced by IL-6/IL-6R complexes), thereby affecting only a portion of IL-6 biologic activity and generating a potentially safer, more potent alternative to existing therapies.
Simultaneous inhibition of TNF and IL-6 systems:
- likely addresses a broad patient population across AIID indications
- may have greater efficacy/potency than inhibition of either system alone
- based on the SCORPION platform may enable pricing advantage (i.e., dual targeting)
Program Overview: X2 CTLA4-Based SCORPION Therapeutics
Trubion’s X2 SCORPION therapeutics are a family of molecules combining the CTLA-4 ectodomain with selected single chain moieties to address the deficiencies of CTLA-4Ig therapy. CTLA-4Ig (abatacept and belatacept) in humans has proven efficacy and safety in rheumatoid arthritis and is in Phase II or III trials in solid organ transplantation, ulcerative colitis, Crohn’s disease, and lupus nephritis. Although CTLA4-based molecules are active in humans, the potency of these molecules can be increased. We have generated a series of SCORPION molecules that combine CTLA4 and other immune modulators (e.g., IL-10) to increase the immunosuppressive activity and to target the inhibition to antigen-presenting cells to reduce potential safety risks.
Program Rationale: X2 SCORPION Therapeutics
Initial molecules of the program combine the CTLA-4 ectodomain with the IL-10 cytokine. IL-10 is an excellent candidate to combine with CTLA4 since IL-10 has been demonstrated to be tolerogenic in the context of CD80/86+ antigen presenting cells and can enhance indoleamine 2,3-dioxygenase (IDO) production, a known immunosuppressant, by APCs. In addition, genetic analyses have linked IL-10 to human inflammatory diseases (e.g., ulcerative colitis). The role of IL-10 in inflammatory bowel diseases has also been observed in preclinical studies (e.g., IL-10 deficient mice spontaneously develop colitis and administration of IL-10 prevents colitis in some preclinical animal models). Since the CTLA4 and IL-10 moieties are physically linked in the SCORPION format, the X2 molecules will potentially deliver IL-10 to where it is needed most, the APC. Initial in vitro results with the CTLA4 X IL-10 molecules demonstrate significantly enhanced activity in comparison to Orencia® and belatacept.