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Engineered protein with enhance antibody targeting and cytotoxic response properties



Mark I. Greene, MD, PhD, FRCP



Antibody-based therapies have demonstrated promising results. Following binding of the mAb to its tumor target, interactions of the Fc-portion with Fc-receptors (Fc-R) expressed by effector cells (e.g. natural killer (NK) cells, macrophages and T-cells) may result in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). It is however clear that mAbs do not exploit the full potential of the immune system as effects are hampered by circulating immunoglobulins (Ig) competing for Fc-R binding spots on immune effector cells, and inadequate tumor-target penetration due to their relatively large size (~150 kDa). Furthermore, binding to inhibitory Fc-R on immune cells may result in internalization of them Ab-tumor target-Fc-R complex reducing its therapeutic efficacy. 



Several strategies have been explored to overcome the limitations listed above. Dr. Greene and his colleagues developed a class of “Grababodies” as working “prototypes”, which carry an IgG binding-domain of Protein A that interacts with Fc region of immunoglobulins (Penn# V4976, Zhang, 2013).  These Grababodies are also engineered to bind to a tumor specific target.  As a result, the Grababodies direct immune effector cell functions towards tumor cells and have potential therapeutic applications. The engineered Grababody for a Her2/neu receptor shows a 50% reduction in tumor volume in mice and is more potent than constructs without IgG binding domains (Figure 1). As protein A is of bacterial origin, the researchers have also developed a humanized IgG binding domain (huZZ) to replace the bacterial portion on Grababodies and reduce immunogenicity.



• Smaller size over regular antibodies

• Glycosylation of the engineered construct is not needed

• Reduced cost of production



Stage of Development

Proof of principle with Her2/neu as the targeted antigen

Confirmed binding of constructs with humanized region “huZZ” binding to IgG


Intellectual Property

US patent 7,119,185

US patent application US 20140234221

Provisional patent application 62/155,567 filed 5/01/2015


Reference Media

Cai et al. Cancer Res, 2013, 73(8): 2619

Zhang. OncoImmunology, 2013, 2(6): e24439



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