ADAPTIRTM Multi-Specific Protein Therapeutic
Emergent’s custom ADAPTIR™ multi-specific protein therapeutic technology extends Emergent’s ADAPTIR™ mono-specific
protein therapeutic technology by combining single-chain binding and effect or domain libraries to crosslink two cell-surface targets or simultaneously bind and neutralize two soluble target antigens. ADAPTIR multi-specific molecules are single chain polypeptides comprising an N-terminal binding domain, an effector domain based on immunoglobulin Fc regions, and a C-terminal binding domain (Figure 1). ADAPTIR multi-specific molecules are produced in standard eukaryotic manufacturing cell lines as disulfide-linked proteins, similar to monoclonal antibodies (mAbs).
Figure 1. Comparison of Molecular Structures of Antibodies vs. ADAPTIR Modular Protein Technology
Features of ADAPTIR Multi-Specific Therapeutics
Choice of Binding Domains: Antibody-derived domains such as single-chain variable fragments (scFv), as
well as proteins from other families such as receptor extracellular domains (ECD) and ligands can be used in
ADAPTIR multi-specific molecules (Figure 2). Other bispecific platforms may be limited to use of only antibody-derived
domains or may require the generation of new binding domains in that format.
Dual Targeting: The unique structure of Emergent’s ADAPTIR multi-specific therapeutics allow them to bind two different
target antigens in a bivalent manner with high affinities.1, 2 The structure also provides spacing and flexibility
between the N- and C-terminal binding domains, allowing ADAPTIR multi-specific molecules to effectively crosslink
two cell-surface targets and drive differentiated signaling.2, 3 Alternatively, ADAPTIR multi-specific therapeutics can
simultaneously bind and neutralize two soluble target antigens.1
Pharmacodynamic and Pharmacokinetic Properties: Effector functions of ADAPTIR multi-specific molecules can be
modulated, similar to ADAPTIR mono-specific molecules—they can be retained, decreased, or enhanced.4, 5, 6 Serum half-life of ADAPTIR multi-specific molecules in mice is similar to that for SMIP molecules; however, constructs with shorter halflives can be produced.
Generation of Multiple Product Candidates: Emergent’s component library of single-chain binding domains
and effector domains allows for rapid construction of a variety of target combinations, a feature that
distinguishes ADAPTIR multi-specific molecules from other bispecific platforms. The human protein sequences used in
ADAPTIR multi-specific molecules are selected for stability, ease of manufacture, optimal spatial orientation in binding
domains, and low immunogenicity potential.
Manufacturing: ADAPTIR multi-specific therapeutics are produced using stable expression systems in standard eukaryotic manufacturing cell lines at levels comparable to SMIP therapeutics (up to 2 g/L).4
Cost of Goods: ADAPTIR multi-specific molecules have been shown in pre-clinical studies to be effective in multiple
disease models at significantly lower concentrations than single agents, so use of ADAPTIR multi-specific molecules may
create a cost of goods advantage over use of single agents.3, 4, 5 Furthermore, production of one ADAPTIR multi-specific
molecule that targets two antigens may be more cost effective than production of two separate therapeutics.
Potential Applications: ADAPTIR multi-specific therapeutics may have potential application in autoimmune and
inflammatory diseases, transplant rejection, oncology, infectious diseases, and other areas of unmet medical need.
Figure 2. Configuration Options for ADAPTIR Multi-Specific Molecules
1. Lofquist A. SCORPION™ molecules: multi-specific binding proteins. IBC’s 4th Annual Beyond Antibodies/Protein Engineering & Design Conference, September 21-23, 2009, San Diego, CA, USA (slide presentation).
2. Tan P, Bader R, Blankenship JW, Hoyos GH, Zhang N, Payandeh E, et al. SCORPION™ molecules block T cell co-stimulation via CD80/CD86 blockade and induce a tolerogenic response via an IL10 agonistic signal. 6th Annual Protein Engineering Summit (PEGS), May 17-21, 2010, Boston, MA, USA (poster presentation).
3. Tan P. Bispecific/multispecific scaffold for autoimmune diseases, oncology and infectious diseases. 7th Annual Protein Engineering Summit (PEGS), May 9-13, 2011, Boston, MA, USA (slide presentation).
4. Mohler KM. SMIP™ and SCORPION™ proteins: novel, mono or multi-specific therapeutic proteins for autoimmune diseases and oncology. Next Generation Protein Therapeutics, September 28-29, 2010, Brussels, BE (slide presentation).
5. Blankenship JW, Strobel S, Tan P, Grosmaire A, Simon C, Clark G, et al. αCD79B×αDR SCORPION molecule: a single-chain, bispecific immunotherapeutic with potent in vitro activity against B-cell lymphoma. 100th Annual Meeting of the American Association for Cancer Research (AACR), April 18-22, 2009, Denver, CO, USA (poster presentation).
6. Wang C, Beckett T, Odegard V, Hussell S, Mohler K, McMahan CJ. Small modular immunopharmaceutical (SMIP™) molecules directed at the TCR complex (CD3) block T cell activation and cause minimal cytokine release in vitro. The American Association of Immunologists 97th Annual Meeting, May 7-11, 2010, Baltimore, MD, USA (poster).
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