ADAPTIRTM Mono-Specific Protein Therapeutic
 
ADAPTIR molecules are mono-specific protein therapeutics recognize and bind to a single antigen target.
Emergent’s custom ADAPTIR platform was designed to address some of the limitations of monoclonal antibodies (mAbs).
 
ADAPTIR mono-specific molecules are single-chain polypeptides comprising three components: a binding domain (VL and VH), a hinge domain, and an effector domain (huFc) (Figure 1). They are designed to address biological imbalances in different disease states. Because of their differentiated structure from mAbs, ADAPTIR mono-specific molecules can engage the disease target in a unique manner and can provide a unique signaling response.1, 2 The modular design enables changes in composition of the individual components to tailor the biological activity of the ADAPTIR mono-specific molecule to fit the desired product profile. Like mAbs, ADAPTIR mono-specific molecules have the potential to bind cell surface targets as well as neutralize soluble antigens that are implicated in human disease.
 
Figure 1. Comparison of Molecular Structures of Antibodies vs. ADAPTIR Modular Protein Technology
 
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ADAPTIR Mono-Specific Therapeutics May Offer Important Features

Structural Characteristics: The binding domains in the ADAPTIR mono-specific platform are closer together (60-80 Aº) than the binding domains in conventional mAbs (95-140 Aº). The different spatial orientation of the ADAPTIR mono-specific molecule compared with a mAb provides the ability to modify signaling responses (e.g., amplifying or extending the duration of the response) compared with mAbs.
 
Molecular Design: The modular design of ADAPTIR mono-specific molecules enables customized balancing of various
biological activities such as target signal induction, complement-dependent cytotoxicity (CDC), and antibody-dependent
cellular cytotoxicity (ADCC).1, 2, 3, 4, 5, 6, 7
 
Biodistribution: The molecular weight of the ADAPTIR mono-specific molecule is approximately one-third less than that of mAbs (105 kD vs. 150 kD). The smaller size of ADAPTIR mono-specific molecules compared with mAbs may increase
their ability to penetrate tissues. This characteristic has been shown to improve transport of macromolecules
within tumors, where diffusion plays a prominent role.8
 
Reliable Manufacturing:  ADAPTIR mono-specific molecules can be produced in large scale using standard mammalian cell lines and conventional processes, similar to mAbs. ADAPTIR mono-specific molecules have been and are currently being manufactured for use in multiple clinical trials in oncology and autoimmune and inflammatory diseases.3, 4, 5, 6
 
Diverse Potential Applications:  ADAPTIR mono-specific molecules may have potential application in the treatment of autoimmune and inflammatory diseases3, 4 oncology5, 6, 9 transplant rejection, infectious diseases, and other areas of unmet medical need.
 
 
REFERENCES
1. 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).
 
2. Mohler KM. SMIP™ and SCORPION™ proteins: novel, mono or multi-specific therapeutic proteins for autoimmune diseases and oncology. Next Generation Protein Therapeutics Summit, June 21-23, 2010, Burlingame, CA, USA (slide presentation).
 
3. Fleischmann R, Cohen S, Pardo P, Dessouki E, Clowse M, Korth-Bradley J, Bhattacharya I, Diehl A, Gourley I. Subcutaneous administration of SBI-087 provides potent B cell depletion in subjects with controlled RA. The European League Against Rheumatism Congress, June 16-19, 2010, Rome, Italy (slide presentation).
 
4. Fleischmann R, Cohen S, Pardo P, Shaw M, Bhattacharya I, Sridharan S, Diehl A, Gourley I. B cell depletion in subjects with controlled systemic lupus erythematosus (SLE) after intravenous or subcutaneous administration of SBI-087. The European League. Against Rheumatism Congress, June 16-19, 2010, Rome, Italy (poster).
 
5. Furman RR, Andritsos L, Flinn IW, Forero-Torres A, Foon KA, Pagel JM, Singhal A, Stromatt SC, Byrd JC. Phase 1, dose escalation study of TRU-016, an anti-CD37 SMIP™ protein in relapsed and refractory CL. American Society of Hematology (ASH ) 52nd Annual Meeting, December 4-7, 2010, Orlando, FL, USA (slide presentation).
 
6. Andritsos L, Furman R, Flinn IW, Foreno-Torres A, Foon K, Flynn JM, Stromatt SC, Byrd JC. A Phase 1 trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SM IP™) protein in relapsed and refractory CL: Early promising clinical activity. American Society of Hematology (ASH ) 52nd Annual Meeting, December 4-7, 2010, Orlando, FL, USA (poster).
 
7. Rafiq S, Cheney C, Thompson PA, Siadak T, Algate P, Cerveny C, Byrd JC, Muthusamy N. Glycovariant CD37 small modular immunopharmaceutical (TruADhanCe™ SM IP) promotes enhanced natural killer cell mediated cytotoxicity against primary chronic lymphocytic leukemia cells. 51st ASH annual meeting, Dec 5-8, 2009, New Orleans, LA, USA (poster).
 
8. Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer. 2007; 109(2): 170-9.
 
9. Abou-Nassar K, Brown JR. Novel agents for the treatment of chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2010; 8(12):886-95.
 

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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

 

 

REFERENCES

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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MVAtorTM (modified vaccinia virus Ankara vector)

MVAtorTM is a flexible, proprietary, viral vector platform based on modified vaccinia virus Ankara (MVA) for delivery of protective or therapeutic antigens. MVA was administered to more than 100,000 subjects as a “prevaccine” prior to use of unattenuated vaccinia. We are using MVAtor to develop novel prophylactic and therapeutic vaccines. MVAtor is derived from an MVA strain isolated before bovine spongiform encephalopathy (BSE) was identified.

 

MVA can infect mammalian cells and goes through early and late stage protein production, but is unable to complete final stages of replication. It can be used to induce an immune response to genes inserted in the virus (recombinant antigens).

 

MVA in Clinical Trials

MVA-based constructs containing recombinant genes for antigen delivery are being evaluated in prevention and treatment of a wide range of infectious diseases and cancers. Human trials have been conducted against infectious diseases including tuberculosis, malaria, and HIV. MVA expressing tumor antigens such as 5T4 and melanoma antigens are being studied in human trials for treatment of cancer.

 

MVA in Manufacturing

Recombinant MVA products have previously been produced in primary chick embryo fibroblasts. In order to standardize production, we have developed a manufacturing process based on the use of a continuous avian cell line, which has the following potential advantages:

 

• Readily scales up to commercial levels,
• Amenable to single-use disposable equipment making transfer of the technology to new manufacturing sites relatively simple as identical equipment can be rapidly installed reducing time and capital cost requirements.

 

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