DELIVERY TECHNOLOGIES
protein conjugates in vivo is better than that of the unmodified protein.
to improve options for haemophilia B patients. Factor IX is a complex protein with 11 disulfide bonds and its deficiency causes Christmas disease. TheraPEG PEGylated Factor IX is active in an in-vivo model and has an extended half-life: PolyTherics has granted an affiliate of Pro Bono Bio, part of the Celtic Pharma Holdings group, an exclusive licence for TheraPEG technology for the latter’s development of this long-acting form of Factor IX. PolyTherics recently signed a further licence agreement with Pro Bono Bio’s affiliate to develop and commercialise a PEGylated version of Factor VIIa, a complex protein with 11 intrachain and one interchain disulfide bonds. The recombinant FVIIa market is estimated at $1.5 billion. PolyTherics has already successfully produced TheraPEG™ FVIIa, utilising its conjugation expertise to develop an efficient process which is being transferred to Pro Bono Bio’s biomanufacturing contractor. The extended alliance between PolyTherics and Pro Bona Bio also includes a feasibility study and licence option agreement for a PEGylated form of Factor VIII.
Other proprietary conjugation technologies
PolyTherics’ HiPEG technology enables PEGylation at polyhistidine utilising the histidine tag of a protein, whilst CyPEG PEGylation occurs at the thiol group on free cysteine and is well suited for engineered proteins and peptides, giving site-specific conjugation and a more stable linkage than maleimide.
These conjugation chemistries can be used with a range of PEG formats, including linear, branched and comb polymers as well as PolyTherics’ own PolyPEG™ polymers. PolyPEG (a technology obtained through the acquisition of Warwick Effect Polymers) is a modular comb-shaped polymer system comprising proprietary low-viscosity PEG- based polymers for half-life extension. The technology overcomes some of the limitations of traditional PEGylated products and works via site-specific attachment using established and novel chemistries. PolyPEG has a flexible polymer architecture as the length of the poly(methacrylic acid) backbone can be varied, as can the length of the PEG teeth. Due to the lower viscosity of the polymers, PolyPEG is well suited for products that need to be dosed at higher protein concentrations. The pharmacodynamic response of PolyPEG
36 sp2 Inter-Active July/August 2012
Enabling better protein-drug conjugates
PolyTherics’ conjugation technology and expertise also enables the production of protein drug conjugates using
heterobifunctional linkers, with the cytotoxic drug or other payload attached to one end of this linker system. Attachment to the protein is via TheraPEG, HiPEG or CyPEG, with the size of the PEG linker being selected to optimise the PK and physicochemical properties of the desired product. The advantages of incorporating PEG into the linker are the reduced propensity to aggregate; improved solubility of the cytotoxic drug and linker reagents; the ability to monitor the conjugation process; and the ease of formulation due to improved stability of the conjugate product. PolyTherics recently established a research collaboration with Spirogen Limited, an oncology-focused company developing DNA sequence-targeted agents, to develop antibody-drug conjugates (ADCs) that combine site-specific conjugation chemistry with Spirogen’s highly potent novel cytotoxic drugs to produce novel ADCs for the treatment of cancer. The two companies will produce the ADCs using TheraPEG to site- specifically conjugate Spirogen’s potent pyrrolobenzodiazepine (PBD) cytotoxic agents – known as ‘warheads’ – to antibodies and antibody fragments. The companies will then test the potency of the resulting ADCs in preclinical models of cancer. PolyTherics and Spirogen will jointly seek partners to develop the most promising ADC candidates that arise from the collaboration.
“The conjugation technologies are highly flexible and are applicable to antibodies and other types of proteins to yield new product formats,” says Burt. “It is possible to quickly combine different binding entities to make bivalent products such as bispecifics, homodimers and heterodimers; combine proteins, peptides, Fabs, other Ab formats, and scaffolds; and to incorporate various linker formats, giving the option to increase half-life. In addition, the technology avoids issues associated with recombinant fusion proteins such as misfolding, low expression or truncated sequences.”
A further technology within the PolyTherics portfolio as a result of the Warwick Effect Polymers acquisition is the targeted delivery approach achieved through application of GlycoPol technology in which proprietary glycopolymers address protein-carbohydrate interactions on specific cells or tissues. Mono-
or disaccharides are attached to a polymer backbone which is conjugated to the therapeutic cargo and thus glycotargeting can be applied to a wide range of cell types including epithelial cells. The conjugation to cargoes is via established or novel chemistries, including PolyTherics’ own disulphide (TheraPEG), cysteine (CyPEG) and poly-histidine (HiPEG) approaches, thus giving wide applicability in terms of therapeutic cargoes: proteins, peptides, oligonucleotides and small molecules can all be delivered.
IP and commercial strategy “PolyTherics has a broad patent portfolio,” says Burt. “Patents for the TheraPEG, PolyPEG and GlycoPol platforms have been granted in many territories including the USA, Europe, India, China, Japan, Korea and Australia, with claims covering the reagents, the conjugation process and protein conjugates. The product-exclusive licences that we grant to our partners mean that they benefit from an additional layer of patent protection on their product, which is an important consideration for development of a biobetter product.
“In order to access our technologies and consider whether they are suitable for a prospective partner’s programme, we conduct feasibility studies and collaborative arrangements, as well as entering into technology evaluation and material transfer agreements,” he adds. “PolyTherics has a flexible collaboration model where conjugation can be undertaken by ourselves or the collaborator, where the polymer and/or reagent plus protocol will be provided and characterisation and in-vitro/in-vivo studies offered. We can provide non-GMP PolyPEG, GlycoPol, TheraPEG, HiPEG and CyPEG reagents for research and early-stage development and will facilitate access to GMP materials and qualified GMP conjugation providers as required according to the partner’s own development strategy. “With a strong commitment to being a go-to company for technologies to enable the development of better biopharmaceuticals, PolyTherics is forging new developmental collaborations,” Burt concludes.
Further information Dr John Burt PolyTherics Ltd The London BioScience Innovation Centre 2 Royal College Street London NW1 0NH United Kingdom Tel: +44 20 7691 4927 Email:
john.burt@polytherics.com Web:
www.polytherics.com
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