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PEER-REVIEWED ARTICLES

First Patient Dosed in Phase I Trial with Pyrrolobenzodiazepine-based Antibody-drug conjugate Targeting AXL in Solid Tumors

The development of proprietary, pyrrolobenzodiazepine-based, antibody-drug conjugates or ADCs targeting AXL, has entered a news phase with the dosing of the first patient in a Phase I clinical trial (NCT03700294). [1]

The investigational agent, called ADCT-601, being developed by Swiss-based (Lausanne |Biopôle) ADC Therapeutics, an oncology drug discovery and development company, is an antibody-drug conjugate composed of a humanized monoclonal antibody (IgG1) against human AXL, site specific conjugated using GlycoConnect™  technology to PL1601, which contains a valine-alanine cleavable linker and the pyrrolobenzodiazepine (PBD) dimer cytotoxin SG3199.

Once bound to an AXL-expressing cell, ADCT-601 is internalized into the cell where enzymes release the PBD-based warhead. The PBD-based warhead has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and ultimately killing the cancer cell.

AXL
AXL is a member of the  tyrosine kinase receptor TAM, a transmembrane receptor highly expressed in solid tumors (e.g. lung, breast, pancreas, glioma and esophageal)  and hematological malignancies (acute myeloid and chronic lymphocytic leukemia).

Expression and activation of AXL is generally associated with poor clinical prognosis. Overexpression  results in resistance to both conventional chemotherapy and targeted therapies, making AXL an attractive target for the development of an ADC to treat AXL-expressing cancers, such as ADCT-601.[2]

Site specific Conjugation
Site of conjugation has implications for both stability and efficacy of an antibody-drug conjugate. ADCT-601 is using GlycoConnect™ site specific conjugation technology, a technology platform developed by Synaffix. The technology uses enzymatic modification of the 2 naturally-occurring glycan anchor points that exist on all antibodies to facilitate efficient, site-specific and stable conjugation of potent anti-cancer molecules using extensively optimized metal-free click chemistry.[3]

The Phase I clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of ADCT-601 in patients with selected solid tumors that are locally advanced or metastatic.

In preclinical studies, ADCT-601 demonstrated potent and specific in vitro and in vivo anti-tumor activity in multiple cancer-derived models with different levels of AXL expression, and was stable and well tolerated.

“AXL is a novel and ideal target for an ADC approach, as it is overexpressed in many solid tumor types. We look forward to exploring the effect of ADCT-601 on patients with selected advanced solid tumors who have failed or are intolerant to any established therapy,” noted Jay Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“With five antibody-drug conjugates in eight ongoing clinical trials for multiple indications, we believe our highly targeted therapies have the potential to meaningfully improve outcomes for patients with solid tumors and hematological cancers,” Feingold added.

Trial design
The clinical trial is designed as an open-label, multicenter, single-arm trial which will include a Phase Ia dose-escalation part followed by a Phase Ib dose-expansion part. The dose-escalation part is designed to determine the maximum tolerated dose of ADCT-601. The identified dose will be evaluated in the dose-expansion part.

Approximately 75 patients are expected to be enrolled in this clinical trial.

Reference
[1] Safety, Tolerability, Pharmacokinetics, and Antitumor Study of ADCT-601 to Treat Advanced Solid Tumors – NCT03700294
[2] Zammarchi F, Havenith K, Chivers S, Hogg PW, Britten C, Dissanayake S, Tyrer P, Bertelli F, et al. Preclinical activity of ADCT-601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting AXL-expressing tumors. AACR Annual Meeting 2018 Online Proceedings.[Poster]
[3] Van Berkel SS, Van Delft FL. Enzymatic strategies for (near) clinical development of antibody-drug conjugates.Drug Discov Today Technol. 2018 Dec;30:3-10. doi: 10.1016/j.ddtec.2018.09.005. Epub 2018 Oct 11. [Pubmed][Article]


Last Editorial Review: January 16, 2019

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Mersana Therapeutics Focuses its Resources on Advancing XMT-1536, its First-in-Class ADC Candidate Targeting NaPi2b

Mersana Therapeutics, a clinical-stage biopharmaceutical company developing a pipeline of antibody-drug conjugates or ADCs designed to target cancers in areas of high unmet need, confirmed that, after a strategic evaluation, the company and its partner Takeda, will discontinue the development of XMT-1522, a  antibody-drug conjugate targeting HER2-expressing tumors, including patients with advanced HER2-positive breast and gastric cancer, as well as advanced breast cancer with low HER2 expression and non-small cell lung cancer (NSCLC).

XMT-1522 contains a proprietary HER2 antibody which is conjugated with Mersana’s Dolaflexin® platform – a Fleximer polymer linked with a novel, proprietary, auristatin payload. The investigational agent provides a drug load of approximately 12 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability.

In a statement, the company confirmed that it will work with investigators to ensure that patients benefiting from XMT-1522 will continue to have access to the therapy as needed.

“On behalf of the Company and our partner Takeda we want to thank the patients and their families for their participation in the study, as well as the investigators and our team for their diligent work on the clinical development of XMT-1522. We are committed to leveraging our proprietary ADC platforms to generate a differentiated pipeline of ADCs,”  said Dirk Huebner, MD, Chief Medical Officer, Mersana Therapeutics.

XMT-1536
Following strategic evaluation, Mersana will focus its resources on the advancement of XMT-1536, a first-in-class ADC candidate targeting NaPi2b.

“While still in early clinical development, we are encouraged with the safety, tolerability, and activity of XMT-1536 as well as the pace at which the current study is advancing. For this reason, we have decided to focus our resources on advancing XMT-1536, our first-in-class ADC candidate targeting NaPi2b, a clinically validated ADC target broadly expressed in ovarian and NSCLC adenocarcinoma, for which there remains a significant unmet medical need,” explained Anna Protopapas, President and CEO, Mersana Therapeutics.

According to Protopapas, XMT-1536 has the potential to play a significant role in the treatment of these diseases. The shift in focus resulted in the discontinuation of the XMT-1522 development program.

“We have made the difficult decision to terminate the further development of XMT-1522 despite a favorable emerging profile of efficacy and tolerability due to the competitive environment for HER2-targeted therapies,” Protopapas added.

Dose escalation study
The data to date from the ongoing XMT-1536 dose escalation study indicate that the trial has reached clinically relevant dose levels but has not yet reached a maximum tolerated dose. The once-every-three-week regimen has been fully explored.  The once-every-four-week schedule is currently being evaluated.  The 20 mg/m2 dose cohort has been shown to be well tolerated and the 30 mg/m2 is currently being evaluated.

As of December 31, 2018, the dose escalation study of XMT-1536, in multiple tumor types, includes eight heavily pretreated and evaluable ovarian cancer patients treated at clinically relevant doses. These patients are unselected for NaPi2b expression and had 3 to 11 (median 6) prior regimens in the platinum resistant or refractory setting. Of these eight patients, two achieved a partial response and the remaining six achieved stable disease. The higher dose levels currently being evaluated, as well as additional patient enrollment, provide the opportunity to further define and optimize the profile of XMT-1536.

Corporate Goals
Mersana expects to select a dose for use in its Phase I expansion studies and to initiate enrollment of patients in the expansion cohorts in the first half of 2019. The expansion cohorts will focus on platinum-resistant ovarian cancer and NSCLC adenocarcinoma. Mersana also plans to utilize its proprietary and validated immunohistochemistry assay to retrospectively determine NaPi2b expression to determine whether a companion diagnostic would facilitate the clinical development of XMT-1536. Mersana also plans to report Phase I dose escalation data in the first half of 2019.

Pipeline Expansion
The Company expects to disclose its next clinical candidate in the second half of 2019 and is targeting the filing of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) in the first half of 2020.

Research and Discovery
Mersana continues to build a pipeline of promising ADCs across a variety of tumor types with significant unmet need, leveraging its three proprietary ADC platforms (Dolaflexin, Dolasynthen, and Alkymer).

Based on the strategic evaluation, Mersana will apply its expertise in ADCs to optimize and validate Immunosynthen, a new platform designed to allow systemic delivery of a potent immunostimulatory molecule to provide optimal efficacy and tolerability.

Collaboration
This week Mersana and Synaffix, a Dutch biotechnology company, confirmed that the two companies have entered into a license agreement in which Mersana gets access to Synaffix’s industry-leading site-specific GlycoConnect™ ADC technology.

“After evaluating several site-specific conjugation platforms, we have chosen Synaffix’s GlycoConnect™ technology for use in future ADC candidates,” Protopapas explained.

“We are excited about the potential of this technology as it is designed not to require additional antibody engineering or cell-line modifications, which would offer us the potential to create site-specific antibodies for use in our ADCs when required,” she concluded.


Last Editorial Review: January 4, 2019

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New ADC Payload Platform – Synaffix Launches toxSYN™

The Netherlands-based biotech company Synaffix, which has developed a proprietary site-specific conjugation platform technology to enable differentiated antibody-drug conjugates or ADCs, launched of a new technology platform of highly potent cytotoxic ADC payloads. The company is expected to integrated this technology platform into its existing ADC platforms. With this expansion, Synaffix becomes a one-stop provider for technologies required to rapidly translate antibodies into proprietary ADC products.

The company focuses on delivering a conjugation platform technology to consistently generate ADCs that are more effective and better tolerated when compared to current clinical-stage ADC conjugation technologies. These proprietary technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes and can be applied directly to an existing antibody without any DNA and or protein engineering.


…We expect this important expansion of our ADC technology to further advance our internal research and facilitate collaborations with a much broader set of companies…


toxSYN™
The new technology platform called toxSYN™, consists of four highly potent payloads, which offer multiple mechanisms of action and a viable path for commercialization when combined with the components of the company’s GlycoConnect™, the company’s proprietary, site-specific and stable antibody conjugation technology that involves enzymes and metal-free click conjugation components, and HydraSpace™, a highly polar ADC-enhancing spacer technology.

The payloads have been clinically validated with well-known efficacy and safety profiles, and were selected to address the two types of biologies that exist across ADC targets which include rapidly-dividing cancer cells as well as quiescent cells, such as cancer stem cells.

Important Expansion
The payloads include a functionalized calicheamicin, a DNA damaging agent called Syneamicin™, a functionalized SN-38, topoisomerase 2 inhibitor, called SYN-38™, a functionalized auristatin E microtubule inhibitor called Synstatin E™ and a functionalized maytansine, a microtubule inhibitor called Syntansine™.

“We expect this important expansion of our ADC technology to further advance our internal research and facilitate collaborations with a much broader set of companies” said Peter van de Sande, CEO of Synaffix.

“By providing these four distinct payloads through our new toxSYN™ platform, we can now enable any company with an existing antibody to rapidly establish a highly-competitive clinical-stage ADC program for its own development pipeline,” Van de Sande added.

Synaffix is backed by a top tier, life science-focused investor syndicate including Aravis, BioGeneration Ventures, BOM Capital and Merck Ventures.


Last Editorial Review: November 7, 2017

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Synaffix Secures End-to-end Patent Protection for GlycoConnect Technology

The Netherlands-based Synaffix, a biotechnology company that has developed a proprietary site-specific platform technology to enable differentiated antibody-drug conjugates (ADCs), has received a key patent that includes the entire GlycoConnect™ process.

The European patent (EP2911699B2), which describing the method used to prepare glycan-conjugated antibody-drug conjugates, significantly expands the IP portfolio of Synaffix beyond several other patents that together provide end-to-end protection of the GlycoConnect™ technology through at least 2035.

The patent covers ADCs prepared by attaching payloads to the trimmed antibody glycan using any metal-free click chemistry approach. The proprietary GlycoConnect™ technology does not require prior antibody engineering, by utilizing two highly efficient enzymes for antibody remodeling together with best-in-class click conjugation of the payload.

The resulting ADCs are significantly more effective and better tolerated than all three major clinical-stage ADC technologies, which has been consistently verified across numerous preclinical benchmarking studies.

The first ADCs that contain Synaffix technology are expected to enter the clinic in 2018.

“Synaffix is a pioneer in the field of glycan-conjugated ADCs and the latest addition to our granted patent estate is a clear testament to that,” noted Floris van Delft, Chief Scientific Officer at Synaffix.

“This further solidifies our dominant position in the field, and highlights Synaffix as the preferred ADC technology provider for companies that wish to rapidly convert their antibody into a best-in-class clinical-stage ADC,” Van Delft added.

Synaffix proprietary technology platform includes GlycoConnect™, the site-specific and stable antibody conjugation technology that involves proprietary enzymes and metal-free click conjugation components, and HydraSpace™, the highly polar ADC-enhancing spacer technology. The technology makes it possible to consistently generate ADCs that are more effective and better tolerated when compared to all three major clinical-stage ADC conjugation technologies. Th

One key benefit of GlycoConnect™ is that it has shown to significantly enhancing the therapeutic index of an ADC on its own. The highly polar properties of HydraSpace™ improve the solubility and stability of the payload and the resulting ADC product, thus enhancing further the therapeutic index of the ADC.

Both technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes and can be applied directly to an existing antibody without any DNA and or protein engineering.

Synaffix is backed by a top tier, life science-focused investor syndicate including Aravis, BioGeneration Ventures, BOM Capital and Merck Ventures.


Last Editorial Review: November 30, 2017

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Synaffix Receives Key Patent for its HydraSpace™ Spacer Technology

Earlier today, Synaffix, a Netherlands based biotechnology company focusing on the development of industry-leading antibody-drug conjugate technology platforms, confirmed receiving a key patent covering its HydraSpace™ spacer technology.  The patent was granted by the United States Patent and Trademark Office (US 9,636,421 B2).

This patent secures the company’s end-to-end patent protection of its ADC technology platform.  The Synaffix’  portfolio of patents covering the core areas of the company’s ADC technology including GlycoConnect™, HydraSpace™ and metal-free click chemistry.

Synaffix’ HydraSpace is a compact and highly polar spacer, which is designed to enhance ADC stability (reduced aggregation) and expand the therapeutic index of an ADC, beyond what is achieved by GlycoConnect alone. The spacer was originally designed to enable efficient attachment of the most challenging hydrophobic payloads, such as pyrrolobenzodiazepines (PBDs), to an antibody.  Additionally, the branching capability of HydraSpace enables a dual-warhead ADC format, which is characterized by the attachment of two distinct payload types to the same antibody.  This approach provides the possibility to deliver two different mechanisms of action to the same cell, which may represent a key strategy in the eradication of cancer stem cells and the treatment of multi-drug resistant forms of cancer.

“HydraSpace has confirmed our expectations as it has demonstrated its potential across numerous comparative studies, including against other mainstream site-specific conjugation technologies.  As such, it represents a key differentiator for ADC product candidates being developed by our collaborators” said Peter van de Sande, CEO of Synaffix.

“The HydraSpace patent now granted, we have secured patent protection through at least 2035 for products developed using our technology,” Van de Sande added.

GlycoConnect, Synaffix site-specific and stable antibody conjugation technology involving proprietary enzymes and metal-free click conjugation reagents, was shown to be capable of significantly enhancing the therapeutic index of an ADC.  In addition, the highly polar properties of HydraSpace improve the solubility and stability of the payload and the resulting ADC product, enhancing further the therapeutic index of an ADC.  Both technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes and can be applied directly to an existing antibody without any engineering.


Last Editorial Review: May 16, 2017

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Synaffix ADCs Significantly Expands the Therapeutic Index vs Cysteine-Engineered ADCs

Netherlands-bases biotechnology company Synaffix BV, which exclusively focuses on the development of novel antibody-drug conjugate (ADC) technology,  confirmed that a new set of head-to-head data demonstrates the potential of its technology to significantly expand the therapeutic index vs cysteine-engineered ADCs.  Supporting data presented during a plenary presentation at the World ADC event in Berlin on Tuesday, February 21, 2017.


“…Our proprietary technology has now demonstrated enhanced therapeutic index also vs what is widely regarded as the most advanced clinical-stage, site-specific ADC technology…”


Conventional antibody-drug conjugates or ADCs produced using earlier conjugation methodologies conjugate a cytotoxic drug to an antibody through the side chains of either surface-exposed lysines or free cysteines generated through reduction of interchain disulfide bonds. Since antibodies contain many lysine residues and cysteine disulfide bonds, the process of conventional conjugation generally produces a heterogeneous mixtures of chemically distinct molecules that vary in both drugs-antibody ratio (DAR) and conjugation sites. This, in turn, presents analytical characterization and manufacturing challenges, resulted from the presence of a mixture of covalent and noncovalently associated light chain and heavy chain subdomains.  The sub-optimal properties of heterogeneous ADCs, each exhibiting different pharmacokinetic, efficacy, and safety profiles, have led to an ongoing effort in improving ADC technology

Researchers at Synaffix have succeeded in doing so and presented data showing superiority of their vs conventional conjugation methodologie. The data they presented resulted from a series of preclinical studies performed in rodents and non-human primates, in a comparative assessment, by an undisclosed collaborator. In these studies different ADCs comprising the same antibody and cytotoxic payload were assembled with either Synaffix’ proprietary GlycoConnect™ and HydraSpace™ technologies or a cysteine-engineered methodology.

Compatibility
Synaffix’ technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes without requiring antibody engineering.

GlycoConnect™ is a site-specific and stable antibody conjugation technology that involves proprietary enzymes and metal-free click conjugation reagents. Research has shown tat GlycoConnect™ is capable of significantly enhancing the therapeutic index of any antibody-drug conjugate on its own.

HydraSpace™ is an ADC-enhancing spacer technology.  The highly polar properties of HydraSpace™ improve the solubility and stability of the resulting ADC product, thus further enhancing the therapeutic index of the ADC.

Enhanced therapeutic Index
“After showing superiority vs the earlier conjugation methodologies used in the currently marketed ADCs, our proprietary technology has now demonstrated enhanced therapeutic index also vs what is widely regarded as the most advanced clinical-stage, site-specific ADC technology” said Floris van Delft, CSO of Synaffix.

“With more than ten engineered-cysteine based ADC programs currently in clinical trials, the new data cultivate further confidence towards the clinical performance of ADCs built using our proprietary technology, as we prepare for the manufacturing of the first clinical batches that will be delivered to patients next year,” Van Delft added.


Last Editorial Review: February 23, 2017

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New Key Patent Covers Synaffix’s Glycan-Conjugated ADC Development Process

Synaffix, a Netherlands-based biotechnology company exclusively focused on the continued advancement of best-in-class ADC technology platforms has received a new key patent for their entire GlycoConnect™ process used to prepare glycan-conjugated ADCs The new patent, which is expected to further strengthening the company’s IP portfolio,has been granted by the United States Trademark and Patent Office (US 9,504,758 B2).

The new patent covers key aspects of GlycoConnect™ site-specific and stable antibody-drug conjugation technology platform developed by Synaffix. The technology is based on attaching payloads directly to the antibody glycan without the need for prior protein engineering.  This process involves proprietary enzymes and metal-free click conjugation reagents and HydraSpace™, the company’s ADC-enhancing spacer technology.

The patented technology was shown to be capable of significantly enhancing the therapeutic index of an ADC on its own. Furthermore, the superiority of this approach has been confirmed in head-to-head comparisons to both U.S. Food and Drug Administration (FDA)-approved antibody-drug conjugates, as well as to ADCs that have been obtained using other mainstream site-specific conjugation approaches.

The highly polar properties of HydraSpace™ improve the solubility and stability of the payload and the resulting ADC product, thus enhancing further the therapeutic index of the ADC. Both technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes without requiring antibody engineering.

“The granting of this patent represents a key milestone in the evolution of our patent portfolio and highlights the strength of our technology,” said Floris van Delft, CSO of Synaffix.

“This patent, together with our granted patent on copper-free click chemistry and the patent applications that cover HydraSpace, will serve an important role for all future drugs developed using our glycan-based ADC technology,” Van Delft concluded.


Last Editorial Review: December 8, 2016

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Synaffix and ADC Therapeutics Sign Agreement for GlycoConnect™ and HydraSpace™ Technologies

Netherlands-based biotechnology company Synaffix has entered into a Commercial License Agreement with ADC Therapeutics for its proprietary site-specific antibody-drug conjugate technologies. The company is exclusively focused on the continued advancement of best-in-class antibody-drug conjugate technology platforms.

ADC Therapeutics is focused on the development of proprietary antibody-drug conjugates incorporating highly potent pyrrolobenzodiazepine (PBD)-based warheads. The company’s clinical and preclinical programs target major types of both hematological malignancies and solid tumors. ADC Therapeutics lead programs, ADCT-301 and ADCT402, are in four phase I clinical trials for certain subtypes of lymphoma and leukemia.


…We look forward to working closely with the ADC Therapeutics… to advance … promising therapeutics to the patients who need them…


Technology platforms
Synaffix’ technology platforms includes GlycoConnect, the site-specific and stable antibody conjugation technology that involves proprietary enzymes and metal-free click conjugation reagents, and HydraSpace, the antibody-drug conjugate enhancing spacer technology.

GlycoConnect was shown to be capable of significantly enhancing the therapeutic index of an antibody-drug conjugate on its own. In addition, the highly polar properties of HydraSpace improve the solubility and stability of the payload and the resulting antibody-drug conjugate product, thus enhancing further the therapeutic index of the antibody-drug conjugate.

Both technologies have demonstrated compatibility with all antibody-drug conjugate payload classes and all IgG isotypes without requiring antibody engineering.

Agreement
Under the terms of the agreement, ADC Therapeutics has been granted a single-target license for one of its preclinical programs and has also been granted an option to take a limited number of additional single-target licenses for potential future programs. Synaffix is also eligible to receive upfront, milestone and royalty payments on a per-target basis.

“We are delighted that ADC Therapeutics has recognized the value of our proprietary antibody-drug conjugate technologies and has elected to incorporate Synaffix technology into one of its preclinical programs,” noted Floris van Delft, CSO at Synaffix.

“The experience of Synaffix and its partners has consistently confirmed that, in preclinical models, our proprietary GlycoConnect™ and HydraSpace™ technologies significantly improved both efficacy and safety as compared to other mainstream site-specific conjugation approaches,” Van Delft added.

“We look forward to working closely with the ADC Therapeutics team to advance these promising therapeutics to the patients who need them,” Van Delft concluded.

Synaffix is backed by a top tier, life science-focused investor syndicate including Aravis, BioGeneration Ventures, BOM Capital and Merck Ventures, the strategic corporate venture capital fund of Merck.


Last Editorial Review: October 20, 2016

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Preclinical Studies Show Significant Improved Therapeutic Index

Synaffix, a Netherlands-based biotechnology company exclusively focusing on the continued advancement of best-in-class and industry leading antibody-drug conjugate (ADC) technology platforms, has competed a new set of preclinical studies that further supports the potential for technology developed by the company to enable safer and more effective targeted cancer therapeutics.

Antibody-drug conjugates use monoclonal antibodies (mAb) to deliver highly potent cytotoxic chemotherapeutic agents targeted to specific tumor cells.  Compared to unconjugated cytotoxic chemotherapy, antibody-drug conjugates improve the therapeutic index or TI, the relationship between (the highest) exposure of a cytotoxic agent and the therapeutic dose, of an anti-cancer agent.[1]  In drug discovery and development, this pharmacodynamic parameter is relevant because it establishes how safe (or toxic) a specific drug is, leading to an appropriately balanced safety–efficacy profile for a given indication.


…[New] experimental findings… highlight the potential…  to address the persistent unmet medical need across a wide variety of cancer types…


Traditional conjugation process
Today, the majority of antibody-drug conjugates in the clinic are based on the conjugation of payload to naturally available amino acid side-chains (i.e. lysine, cysteine). While the majority of these ADCs use a linkage to the thiol of cysteines on the antibody, a lesser number of these drug candidates utilize chemistry to surface lysines of the antibody. This generally results in a stochastic distribution of drug−antibody ratio or DAR between 0 and 8. [1][2]

synaffix-illustration-ADCs1
Figure 1.0: With a suite of advanced tools for the design and development of antibody-drug conjugates Synaffix offers scientists a technology that can be used to develop ADCs targeted against a wide variety of cancer types.

Emerging technologies
A better understanding of conjugation chemistry and the underlying biologies have helped scientists advance the technologies used in the development of first- and second-generation antibody-drug conjugates, leading to new approaches, including considerable emphasis on site-specific conjugation, to ensure homogenous ADCs with well-defined DARs. [3][4]

New site-specific approaches being developped not only increase the homogeneity of antibody-drug conjugates, they also enable novel bio-orthogonal chemistries* based on reactive moieties other than thiol or amine.  In turn, these novel approaches broaden the diversity of linkers used, leading to better linker design for future generations of ADCs. [2][8]

Among these emerging technologies is Synaffix’s novel, proprietary, approach, which, for example, includes a robust, generally applicable, nongenetic technology designed to convert monoclonal antibodies into stable and homogeneous ADCs.[4]

The data in Synafix’ preclinical studies, based on the company’s latest R&D efforts, demonstrates that the company’s proprietary platform technologies, GlycoConnect™ and HydraSpace™, generate ADCs with significantly improved therapeutic index when directly compared to brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), two approved ADCs for the treatment of multiple lymphoma indications and HER2-positive breast cancer, respectively.[5]

synaffix-illustration-GlycoConnect2
Figure 2.0: GlycoConnect™ chemoenzymatic antibody remodeling and conjugation process developed by Synaffix.

Technology Platforms
GlycoConnect, Synaffix’ robust chemoenzymatic technology platform, is a site-specific and stable antibody conjugation technology that allows for efficient antibody-to-ADC conversion by anchoring a payload to the antibody’s glycan at asparagine-297 (Asn-297).

Human immunoglobulins, including Immunoglobulin G (IgG), the most prominent antibody in humans, are mainly glycosylated at the asparagine residue at position 297 (Asn 297) of the heavy chain CH2 domain.

Synaffix’ process involves proprietary enzymatic N-glycan remodeling with one azide, forming an anchor point for the copper-free click attachment of a cytotoxic payload.

The antibody remodeling includes a two-step approach.  In the first step the enzyme trims the glycan. In the second step the enzyme installs a proprietary small molecule substrate bearing a functional handle, which will be used during subsequent conjugation. In this process, the proprietary azide-based enzymatic substrate preserves the high reactivity and selectivity afforded by conjugation via click chemistry.

Since aromatically stabilized structures typically come with an order of magnitude higher stability than non-aromatic structures, the aromatically-stabilized triazole linker, formed during the second reaction, offers improved safety and efficacy profiles. As a result, a higher level of cytotoxic payloads reach the targeted cancer cell, increasing efficacy, while minimizing the potential of premature detachment in circulation and improving the safety profile.

Enhancing therapeutic index
GlycoConnect was shown to be capable of significantly enhancing the therapeutic index of an antibody-drug conjugate on its own.

Using novel proprietary linkers, the highly polar properties of HydraSpace-technology, an ADC-enhancing spacer technology which enables conjugation of highly hydrophobic payloads, improves the solubility and stability of the payload.

One of the challenges in the development of antibody-drug conjugates, is that most of the cytotoxic payloads are hydrophobic. As a result, linking them to a monoclonal antibody with an additional hydrophobic moiety may create problems due to aggregation. [6]

Since ADC aggregates are insoluble, such aggregates can limit achievable drug loading onto the antibody. In addition, some studies suggest that ADC aggregates are sequestered in the liver, leading to hepatotoxicity and is linked to increased immunogenicity.[6]

However, in contrast to standard approaches, the highly polar properties of HydraSpace-technology enables the most challenging hydrophobic payloads to be efficiently conjugated to antibodies.

According to Synaffix’ s scientists, the result is the generation of stable ADCs at the desired drug-to-antibody ratio (a homogeneous DAR 2 or DAR 4).  This novel technology makes it possible to increase drug loading using two different drugs with varying mechanism of action (MOA) to be incorporated into a single therapeutic ADC (DAR 2+2 “dual-payload” ADCs) by a single conjugation event. [4][7]

Metal-free Click Chemistry
Metal-free click chemistry is widely used by researchers in pharma, biotech and academia.  This chemistry offers a unique capability for rapid, selective and stable conjugation of complex macromolecules.

Synaffix’ scientists have extensively optimized metal-free click chemistry between cyclooctynes and azides in conjunction with GlycoConnect for conjugation of potent cytotoxins site-specifically to antibodies.

The resulting antibody-drug conjugates feature an aromatically stabilized triazole. Given its high stability, the resulting chemistry provides a powerful alternative to cysteine-maleimide conjugation chemistry currently used in the majority of antibody-drug conjugates in the clinic.

Furthermore, pre-clinical studies have demonstrated the versatility of GlycoConnect across a range of different antibody isotypes and linker-to-payload combinations as well as excellent in vivo efficacy and high tolerability.  This approach paves the way for the next generation of antibody-drug conjugates with an improved therapeutic index.[7]

Synaffix’ scientists were also able to seamlessly upscale GlycoConnect, further confirming manufacturability.

Key metric
“Improvement in the therapeutic index is a key metric in the quest for superior ADCs. What is exciting about our technology is that we can now consistently demonstrate in preclinical models of both liquid and solid tumors that if we connect the same antibody and payload from each [of the] commercially-available ADC products using our proprietary technology, we are able to increase the efficacy of the drug as well as its safety and tolerability,” noted Floris van Delft, PhD, co-founder and Chief Scientific Office at Synaffix.

“Our experimental findings to date … highlights the potential of our technology to address the persistent unmet medical need across a wide variety of cancer types,” Van Delft added.


Last Editorial Review: July 28, 2016

Note: * Coined by Carolyn R. Bertozzi, the term bio-orthogonal chemistries refer to chemical reactions occurring inside of living systems without interfering. These reactions neither interact with nor interfere with native biochemical processes. [8]

Featured Image: Scientists in Research Laboratories. Courtesy: © Fotolia Photo. Used with permission. Figure 1: Suite of Advanced tools for the development of antibody-drug conjugates. Figure 2: GlycoConnect chemoenzymatic antibody remodeling and conjugation process. Courtesy Figure 1 and Figure 2: © Synaffix BV, The Netherlands.  Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Synaffix’s New High Potency Lab now Fully Operational to Support Growing Collaboration With Biotech and Pharma

Late last week, Synaffix, a Dutch biotechnology company backed by a top tier, life science-focused, investor syndicate and the strategic corporate venture capital fund of Merck KGgA, announced that it had finalized the construction of it’s high potency laboratory.    

The new laboratory facilitates the synthetic modification and safe handling of highly potent anti-cancer payloads and their site-specific attachment to antibodies.  And it allows the company, which focuses exclusively on the development of novel, industry-leading antibody-drug conjugate (ADC) technology, to generate gram-scale batches of ADCs for preclinical use.

Capabilities
“The …[opening of our] high potency laboratory marks an important event in the evolution of the company’s research and development capabilities,” explained Floris van Delft, Chief Scientific Officer of Synaffix and special professor of Bioconjugate Chemistry at Wageningen University in Wageningen, The Netherlands. “Coupled with the preexisting speed of our GlycoConnect™ technology to generate ADC material as fast as couple of weeks, the increased scale and ongoing commitment to safety will further enhance our ability to support a growing number of collaborations with biotech and pharma companies,” Van Delft added.

Technology
The company’s two proprietary technology platforms, GlycoConnect and HydraSpace™, expand the therapeutic index (TI) of ADCs without the need for antibody engineering, while, at the same time, retaining the versatility to utilize any IgG isotype and payload class.

Site-specific conjugation
GlycoConnect represents a site-specific conjugation technology that employs the native antibody glycan for efficient attachment of cytotoxic payloads, resulting in ADCs that come with an expanded therapeutic index compared to current, marketed, approaches and novel ADCs in preclinical and clinical development. [1]

Today, the vast majority ADC in clinical trials are based on conjugation of a payload to naturally available amino acid side-chains through solvent exposed lysine residues (via succinimide ester derivatization) or interchain cysteine residues (maleimide chemistry), leading to a stochastic distribution of drug–to-antibody ratio (DAR) between 0 and 8 (with an average between 3 – 4). [2][3] However, studies have shown that random conjugation has a negative impact on efficacy of an antibody-drug conjugate.  ADCs with a DAR >4 have an increased tendency to aggregate. This negatively impacts the in vivo characterization and clearance rates and results in a low therapeutic index.[3]

A better understanding of conjugation chemistry and the underlying biologies have helped scientists advance the technologies used in the development of first- and second-generation ADCs, leading to new approaches, including considerable emphasis on site-specific conjugation, to ensure homogenous ADCs with well-defined DARs. [3] Among these emerging technologies is Synaffix’s novel, proprietary, approach, which, for example, includes a robust, generally applicable, nongenetic technology designed to convert monoclonal antibodies (mAbs) into stable and homogeneous ADCs.

Starting from a non engineered, native, monoclonal antibody, a chemoenzymatic protocol allows for the highly controlled attachment of any given payload to the N-glycan residing in the Cγ2 domain [asparagine 297 (Asn297)].  The process comprises two stages, including enzymatic remodeling (trimming and tagging with azide), followed by ligation of the payload based on copper-free click chemistry.[4]

The technology is applicable to any immunoglobulin G (IgG) isotype irrespective of glycosylation profile. Application to trastuzumab and maytansine, both components of ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) a targeting antbody-drug conjugates for the treatment of patents with HER2-positive metastatic breast cancer, demonstrates a favorable in vitro and in vivo efficacy for Synaffix’s GlycoConnect ADCs. The superiority of the native glycan as attachment site was further demonstrated by in vivo comparison to a range of trastuzumab-based glycosylation mutants.[4]

According to scientists at Synaffix, side-by-side comparison of the copper-free click probes bicyclononyne (BCN) and a dibenzoannulated cyclooctyne (DBCO) confirmed a surprising difference in conjugation efficiency in favor of BCN.[4]  Optimizing metal-free click chemistry between cyclooctynes and azides in conjunction with Synaffix’s GlycoConnect for conjugation of potent cytotoxins site-specifically to monoclonal antibodies, results in a conjugate featuring an aromatically stabilized triazole which, by virtue of its high stability, provides a powerful alternative to cysteine-maleimide conjugation chemistry.

The introduction of electron-withdrawing fluoride substitutions onto the azide further enhances the technology. In various studies, the resulting mAb-conjugates were  highly stable, which in combination with the demonstrated efficacy warrants ADCs with a superior therapeutic index.[4]

Payload-enhancing linker
The second technology being developed by Synaffix is HydraSpace, a payload-enhancing linker designed further differentiate the GlycoConnect technology from alternative approaches.  This process does not require genetic modification of the antibody.  This key advantage significantly reduces development timelines, and, as a result, enables proof of concept ADCs to be generated from existing antibody material in a matter of weeks while retaining absolute versatility with respect to the combination of antibodies and payloads possible.[4]

Boosting efficacy
Comparing the highly polar nature of HydraSpace to polyethylene glycol (PEG) shows a significantly increase in the conjugation efficiency of highly hydrophobic payloads, while, at the same time, reducing the aggregation propensity of the resulting ADC. Furthermore, scientists have, in several occasions, seen a significant boost in efficacy of ADCs, compared to its PEG-based alternatives.[4]

Increase drug loading
HydraSpace uses novel proprietary linkers. The technology enables the most challenging hydrophobic payloads to be efficiently conjugated to antibodies. According to Synaffix’ s scientists, the result is the generation of stable ADCs at the desired drug-to-antibody ratio (a homogeneous DAR 2 or DAR 4). Furthermore, the novel technology makes it possible to increase drug loading using two different drugs with varying mechanism of action to be incorporated into a single therapeutic ADC (DAR 2+2 “dual-payload” ADCs) by a single conjugation event.  Studies have shown that this designed provides superior outcomes compared to the co-administration of the two active components separately.[4]

During the upcoming ADCs and Cancer Immunotherapy Summit organized by the Vonlanthen Group, which is being held in Vienna, Austria on February 25 – 26, 2016, Synaffix’s CSO Van Delft will present a case study discussing how non-genetic glycan conjugation leads to ADCs with an improved therapeutic index.

“We’re proud to share [our] results … [The] data … supports the superior therapeutic index of ADCs achieved using our proprietary technology compared to [currently] marketed ADCs. With the scalability required for clinical and commercial manufacturing already established … our technology is … just one step away from …. clinical trials,” Van Delft concluded.


Last Editorial Review: February 24, 2016

Featured Image: Laboratory glass. Courtesy: © Fotolia Photo. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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