Japanese pharmaceutical and biotechnology company Kyowa Kirin has expanded its license agreement with The Netherlands based Synaffix with one new antibody-drug conjugates (ADC) target added to its research evaluation and development efforts under an original agreement signed in August 2021, to a total of three ADC programs. In addition Kyowa Kirin exercised its option to take exclusive development and commercialization rights for an undisclosed ADC target under the terms of the expanded agreement.

The expansion follows a successful initial research collaboration between the companies whereby Kyowa Kirin has demonstrated a highly competitive preclinical therapeutic index for its lead program under this collaboration, prepared from a Kyowa Kirin antibody using Synaffix’s ADC technology.

The original agreement, signed in August 2021, enabled Kyowa Kirin to evaluate two of its antibodies as proprietary ADC therapeutic candidates within its pipeline.

Technology
The technology licensed from Synaffix include GlycoConnect™, HydraSpace™, and multiple toxSYN™ linker-payloads, which allow for the drug-to-antibody ratio (DAR) to be tailored to 1, 2 or 4 to optimize the therapeutic index of the ADC.

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  • GlycoConnect™ is a conjugation technology that exploits the native antibody glycan for site-specific and stable payload attachment and is tunable to drug-to-antibody ratio (DAR) 1, 2 or 4 formats. The technology, applicable to any IgG isotype irrespective of glycosylation profile, allows for the highly controlled attachment of any given payload to the N-glycan residing at asparagine-297. It uses the globally conserved N-glycosylation site to generate stable and site-specific ADCs based on enzymatic remodeling (trimming and tagging with azide) and metal-free click chemistry. In the development of the technology, scientists have shown that engineered endoglycosidase and a native glycosyl transferase enable highly efficient glycan remodeling by incorporating a novel sugar substrate 6-azidoGalNAc. In addition, metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants.[1][2]
  • HydraSpace™ is a compact and highly polar spacer technology that is designed to further enhance therapeutic index, particularly with hydrophobic payloads. An evaluation of the therapeutic potential of GlycoConnect™, in combination with HydraSpace™, with [ado-] trastuzumab emtansine (Kadcyla®; Genentech/Roche) demonstrate significantly improved in vitro and in vivo efficacy and tolerability for GlycoConnect ADC.[1][2]
  • toxSYN™ is a linker-payload platform that spans key, validated Mechanism of Actions (MOA) for ADC product development, including SYNtecan E™ (topoisomerase inhibition using an exatecan payload), SYNeamicin G™ (DNA damaging using a calicheamicin γ1payload), and SYNtansine™ (microtubule inhibition, using N-6-aminohexanoyl-maytansine (ahx-maytansine) as payload), a among other linker-payloads.

The combination of these three technologies provides developers with a “one stop” and easy-to-use ADC technology platform, allowing any antibody developer to develop its own proprietary ADC and any ADC developer to expand its pipeline further and increase its competitive position. The platform technology enables a rapid timeline to clinic due to the established supply chain of technology components.

Agreement
Under the terms of the amended license agreement, Synaffix will receive an immediate payment of US $ 5 million and is eligible to receive total potential payments for the first ADC program alone of up to US $ 171m plus royalties on commercial sales.

“We’re committed to realizing the successful creation and delivery of life-changing value and believe that Synaffix’s cutting-edge ADC technologies will enable us to rapidly generate multiple potential ADC pharmaceutical candidates, spanning different mechanisms of action and optimal structures, under a single, simple technology access license and result in providing new therapeutic options for people living with disease,” said Yoshifumi Torii, Executive Officer, Vice President, Head of R&D Division of Kyowa Kirin.

“We are thrilled with the successful ADC data, expansion of this license agreement and to see a leading global pharmaceutical company like Kyowa Kirin deploying Synaffix ADC technology in order to fulfill its mission of improving the lives of patients with cancer worldwide,” concluded Floris van Delft, Ph.D., Chief Scientific Officer of Synaffix.

Highlights of prescribing information
[Ado-] trastuzumab emtansine (Kadcyla®; Genentech/Roche)[Prescription information]

Reference
[1] Wijdeven MA, van Geel R, Hoogenboom JH, Verkade JMM, Janssen BMG, Hurkmans I, de Bever L, van Berkel SS, van Delft FL. Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. MAbs. 2022 Jan-Dec;14(1):2078466. doi: 10.1080/19420862.2022.2078466. PMID: 35634725; PMCID: PMC9154768.
[2] van Geel R, Wijdeven MA, Heesbeen R, Verkade JM, Wasiel AA, van Berkel SS, van Delft FL. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody-Drug Conjugates. Bioconjug Chem. 2015 Nov 18;26(11):2233-42. doi: 10.1021/acs.bioconjchem.5b00224. Epub 2015 Jun 10. PMID: 26061183.

Featured image: GlycoConnect™ design easily matches payload potency with the most appropriate drug-antibody ratio (DAR). In this case DAR 4:1. Image courtesy: © 2021 Synaffix BV. Used with permission.

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