ADCs for PBD
May 2012
by Lloyd Dunlap  |  Email the author


LondonóPolyTherics Ltd. has formed a research collaboration with Spirogen Ltd., an oncology-focused company developing DNA-sequence targeted agents, to develop antibody-drug conjugates (ADCs) that combine PolyTherics' proprietary site-specific conjugation chemistry with Spirogen's cytotoxic drugs to produce novel ADCs for the treatment of cancer.  
It's a first-time collaboration for the two companies, notes PolyTherics CEO John Burt.

"However, as two of London's leading biotech companies, we are well known to each other, not least through our mutual connections with London School of Pharmacy and University College London. The collaboration arose as we made an active push into the ADC space and recognized the value of combining our TheraPEG linker technology with novel cytotoxic payloads as a means to develop superior ADC products. Consequently, the potency of Spirogen's novel pyrrolobenzodiazepines (PBD) molecules made them attractive warheads to pursue in combination with the TheraPEG site-specific conjugation technology," Burt says.

Under the terms of the collaboration, the two companies will produce the ADCs using PolyTherics' proprietary TheraPEG linker technology to site-specifically conjugate Spirogen's potent PBD cytotoxic agents to antibodies and antibody fragments. The companies will then test the potency of the resulting ADCs in preclinical cancer models.

"PolyTherics and Spirogen will contribute their own resources to the collaboration," Burt says. "As we establish proof of concept in the relevant in-vitro and in-vivo preclinical studies, we will jointly seek partners to further develop these products and apply our respective technologies to our partners' ADC programs. At this stage, the economics of these partnering deals have yet to be established, but we have major biotech and pharma companies interested in the combination of the TheraPEG linker technology with novel payloads."  
The structured activity relationships of PBDs have been studied for decades and have led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. PBDs have been found to be potent antitumor agents that exhibit minimal bone marrow depression. They are relatively small molecules that exert their antitumor activity by covalently binding to the DNA in the minor groove. Due to their shape, they cause minimal disruption to the DNA helix. It is believed that the formation of the DNA-PBD adduct inhibits nucleic acid synthesis and causes excision-dependent single- and double-stranded breaks in the DNA helix.

Utilization of the appropriate linker technology is recognized as a critical success factor in the development of a potent, efficacious and well-tolerated ADC product, Burt states. TheraPEG linker technology, which achieves site-specific conjugation to a disulphide bond of the antibody or other targeting protein, can provide a superior conjugation technology over alternative chemistries that rely on either non-site- specific conjugation, sequence modification with non-natural amino acids or less stable linker chemistry based on maleimide conjugation, he says.

"TheraPEG conjugation chemistry will enable site-specific attachment to the native disulphide bonds of proteins and has been used to extend the half-life through conjugation of varying sizes and formats of PEG (polyethylene glycol) to therapeutic proteins such as interferon beta for the treatment of multiple sclerosis (in partnership with Nuron Biotech) and Factor IX for the treatment of hemophilia B (in partnership with Celtic Pharma Holdings). Reduction and rebridging of the disulphide bond using TheraPEG reagents is efficient, site-specific and can be applied for half-life extension (with PEG or PolyTherics' proprietary low viscosity comb polymer, PolyPEG) and for the construction of antibody-drug conjugates, as in the case of this collaboration with Spirogen."
Chris Martin, CEO of Spirogen, adds, "We believe that ADCs will represent a significant medical breakthrough in cancer therapy over the coming decade, and that PolyTherics' TheraPEG conjugation technology will broaden the applications where our PBD warheads and linkers can create highly potent potentially market-leading ADC candidates."
Code: E051206

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