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Infectious Diseases

Respiratory Diseases

Fusion protein

Recombinant protein

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Disease Domain	Count

Infectious Diseases	3

Top 5 Drug Type	Count

Fusion protein	2
Recombinant protein	1

Top 5 Target	Count

DPP-4(Dipeptidyl peptidase IV)	1
ANTXR2(ANTXR cell adhesion molecule 2)	1
ACE2(Angiotensin-converting enzyme 2)	1

AbstractBackgroundAs a major cause of a myriad of superficial and invasive infections worldwide, Staphylococcus aureus is a master of immune evasion, with the complement system being a primary target. Previously, we have shown that S. aureus surface protein SdrE binds the regulator Factor H (FH) to inhibit complement. Taking advantage of this interaction, we tested the effect of a fusion protein comprised of FH(18–20) fused to an IgG Fc on complement-mediated opsonophagocytosis and killing of methicillin resistant S. aureus.MethodsFusions were produced via the ΔXT/FT Nicotiana benthamiana plant expression system. Binding dynamics were examined via immunoblotting, fluorescence and ELISA. The effect of fusions on complement activation was determined by examining C3-fragment opsonization of S. aureus (total C3, C3b, iC3b) and subsequent C5a generation. The effect of fusions on S. aureus survival was assessed using an opsonphagocytosis assay with human polymorphonuclear cells.ResultsS. aureus bound significantly more FH-Fc compared to Fc-controls, and competed with serum FH for S. aureus binding. FH-Fc outperformed a complement inactive fusion variant in C3-fragment deposition and C5a generation, signifying an active role for the Fc region of FH-Fc. For 75% (3/4) of clinical isolates tested, FH-Fc significantly reduced S. aureus survival. Clinical isolates were all sdrE positive, sequence type 8, SCCmec IVa and Panton-Valentine Leukocidin (pvl) positive).ConclusionFH-Fc competitively inhibited serum FH from S. aureus binding and increased complement-mediated opsonophagocytosis and killing of CA-MRSA. Future studies will focus on enhancing the efficacy of FH-Fc fusion molecules as potential anti-staphylococcal therapeutics.Supported by a grant from the US Department of Defense, USAMRDC (W81XWH-19-1-0119).

01 May 2021·The Journal of Immunology

A Factor H-Fc fusion protein competes with serum FH for binding to Staphylococcus aureus and boosts complement-mediated opsonization

Author: Wycoff, Keith ; Sage, Megan A.G. ; Cranmer, Katelyn D. ; Sharp, Julia A.

AbstractStaphylococcus aureus is a significant human pathogen that causes a multitude of superficial and invasive infections worldwide. As antibiotic resistance is increasing, novel therapies are in dire need. As a master of immune evasion, S. aureus produces several virulence factors to persist in the host. A primary target of staphylococcal immune evasion is the Complement system, a component of innate immunity central to controlling bacterial infections. We have previously shown that S. aureus binds Complement regulator Factor H (FH) via surface protein SdrE to inhibit Complement. To address the need for novel therapeutics and take advantage of the SdrE:FH interaction, we tested the binding and downstream effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG1 Fc using a S. aureus clinical isolate known to bind FH.S. aureus bound significantly more FH-Fc than Fc-control proteins indicating a greater affinity for SdrE compared to S. aureus Fc-binding proteins Protein A and Sbi. In the presence of normal human serum, FH-Fc competitively bound to S. aureus and reduced S. aureus recruitment of serum FH compared to Fc-control. When examining the effect of FH-Fc on complement-mediated opsonization of S. aureus, treatment with FH-Fc resulted in a slight increase in C3-fragment deposition and a significant increase in C5a generation compared to control. This may be attributed to the cumulative effect of serum FH displacement plus a boost in classical pathway activation via additional Fc presence afforded by SdrE:FH-Fc binding. Taken together, these data support FH-Fc as a potential anti-staphylococcal therapeutic. Future studies will explore how FH-Fc affects S. aureus survival when challenged with phagocytes.

01 Aug 2016·Journal of Biological ChemistryQ2 · BIOLOGY

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation

Q2 · BIOLOGY

Article

Author: Zhang, Jianbing ; Weider, Elodie ; Ashraf, Yahya ; Susan-Resiga, Delia ; Seidah, Nabil G ; Hamelin, Josée ; Asselin, Marie-Claude ; Wycoff, Keith L ; Nimesh, Surendra ; Prat, Annik ; Essalmani, Rachid

Single domain antibodies (sdAbs) correspond to the antigen-binding domains of camelid antibodies. They have the same antigen-binding properties and specificity as monoclonal antibodies (mAbs) but are easier and cheaper to produce. We report here the development of sdAbs targeting human PCSK9 (proprotein convertase subtilisin/kexin type 9) as an alternative to anti-PCSK9 mAbs. After immunizing a llama with human PCSK9, we selected four sdAbs that bind PCSK9 with a high affinity and produced them as fusion proteins with a mouse Fc. All four sdAb-Fcs recognize the C-terminal Cys-His-rich domain of PCSK9. We performed multiple cellular assays and demonstrated that the selected sdAbs efficiently blocked PCSK9-mediated low density lipoprotein receptor (LDLR) degradation in cell lines, in human hepatocytes, and in mouse primary hepatocytes. We further showed that the sdAb-Fcs do not affect binding of PCSK9 to the LDLR but rather block its induced cellular LDLR degradation. Pcsk9 knock-out mice expressing a human bacterial artificial chromosome (BAC) transgene were generated, resulting in plasma levels of ∼300 ng/ml human PCSK9. Mice were singly or doubly injected with the best sdAb-Fc and analyzed at day 4 or 11, respectively. After 4 days, mice exhibited a 32 and 44% decrease in the levels of total cholesterol and apolipoprotein B and ∼1.8-fold higher liver LDLR protein levels. At 11 days, the equivalent values were 24 and 46% and ∼2.3-fold higher LDLR proteins. These data constitute a proof-of-principle for the future usage of sdAbs as PCSK9-targeting drugs that can efficiently reduce LDL-cholesterol, and as tools to study the Cys-His-rich domain-dependent sorting the PCSK9-LDLR complex to lysosomes.

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Pipeline

Pipeline Snapshot as of 26 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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1

2

Preclinical

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5

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

PBI 220 ( ANTXR2 )	Anthrax More	Preclinical
ACE2-Fc COVID-19 therapeutic (Planet Biotechnology) ( ACE2 )	COVID-19 More	Preclinical
DPP4-Fc ( DPP-4 )	Coronavirus Infections More	Discovery
RhinoRx(Planet Biotechnology, Inc.) ( ICAM-1 )	Rhinovirus infection More	Discontinued
Cat hair allergen extract(Planet Biotechnology, Inc.)	Hypersensitivity More	Discontinued