ADCs for PBD

PolyTherics will collaborate with Spirogen to develop novel anti-cancer antibody-drug conjugates

Lloyd Dunlap
London—PolyTherics Ltd. has formed a research collaborationwith Spirogen Ltd., an oncology-focused company developing DNA-sequencetargeted agents, to develop antibody-drug conjugates (ADCs) that combinePolyTherics' proprietary site-specific conjugation chemistry with Spirogen'scytotoxic drugs to produce novel ADCs for the treatment of cancer.
 
 
It's a first-time collaboration for the two companies, notesPolyTherics CEO John Burt.

"However, as two of London's leading biotech companies, we are well known toeach other, not least through our mutual connections with London School ofPharmacy and University College London. The collaboration arose as we made anactive push into the ADC space and recognized the value of combining ourTheraPEG linker technology with novel cytotoxic payloads as a means to developsuperior ADC products. Consequently, the potency of Spirogen's novelpyrrolobenzodiazepines (PBD) molecules made them attractive warheads to pursuein combination with the TheraPEG site-specific conjugation technology," Burtsays.

Under the terms of the collaboration, the two companies will produce the ADCsusing PolyTherics' proprietary TheraPEG linker technology to site-specificallyconjugate Spirogen's potent PBD cytotoxic agents to antibodies and antibodyfragments. The companies will then test the potency of the resulting ADCs inpreclinical cancer models.

"PolyTherics and Spirogen will contribute their own resources to thecollaboration," 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 developthese products and apply our respective technologies to our partners' ADCprograms. At this stage, the economics of these partnering deals have yet to beestablished, but we have major biotech and pharma companies interested in thecombination of the TheraPEG linker technology with novel payloads."
 
 
The structured activity relationships of PBDs have been studiedfor decades and have led to a detailed understanding of how to introducestructural modification to enhance biological activity and potency. PBDs havebeen found to be potent antitumor agents that exhibit minimal bone marrowdepression. They are relatively small molecules that exert their antitumoractivity by covalently binding to the DNA in the minor groove. Due to theirshape, they cause minimal disruption to the DNA helix. It is believed that theformation of the DNA-PBD adduct inhibits nucleic acid synthesis and causesexcision-dependent single- and double-stranded breaks in the DNA helix.

Utilization of the appropriate linker technology is recognized as a criticalsuccess factor in the development of a potent, efficacious and well-toleratedADC product, Burt states. TheraPEG linker technology, which achievessite-specific conjugation to a disulphide bond of the antibody or othertargeting protein, can provide a superior conjugation technology overalternative chemistries that rely on either non-site-specific conjugation,sequence modification with non-natural amino acids or less stable linkerchemistry based on maleimide conjugation, he says.

"TheraPEG conjugation chemistry will enable site-specific attachment to thenative disulphide bonds of proteins and has been used to extend the half-lifethrough conjugation of varying sizes and formats of PEG (polyethylene glycol)to therapeutic proteins such as interferon beta for the treatment of multiplesclerosis (in partnership with Nuron Biotech) and Factor IX for the treatmentof hemophilia B (in partnership with Celtic Pharma Holdings). Reduction andrebridging 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 ofantibody-drug conjugates, as in the case of this collaboration with Spirogen."
 
Chris Martin, CEO of Spirogen, adds, "We believe that ADCs will represent asignificant medical breakthrough in cancer therapy over the coming decade, andthat PolyTherics' TheraPEG conjugation technology will broaden the applicationswhere our PBD warheads and linkers can create highly potent potentially market-leadingADC candidates."

Lloyd Dunlap

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