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PEGs and Antibody-drug Conjugates a Versatile Approach

Polyethylene Glycol (PEG), sometimes referred to as polyethylene oxide (PEO), consists of repeating ethylene oxide units. Being a nondenaturing water-soluble condensation polymer of ethylene oxide and water, PEGs have several chemical properties that make it useful for biological, chemical and pharmaceutical applications.

Being non-toxic and non-immunogenic, PEGs are very suitable for biological applications because they do not initiate an immune response. This means that they can be added to media and attached to surfaces and conjugated to molecules without interfering with cellular functions or target immunogenicities. As a result, they are often used for protein precipitation and activated for binding to polypeptides and proteins. [1][2]

The useful characteristics of PEG Linkers have been increasingly recognized in bioconjugation, biolabeling and ADC research and development. This is, in part, due to their water solubility, lack of toxicity and well-defined chain lengths.

Antibody-drug Conjugates
PEG-linkers are particularly attractive as a linker for conjugation. Water solubility, lack of toxicity; low immunogenicity and well defined chain lengths and molecular weights are specific characteristics of PEG moieties relevant to pharmaceutical applications.

In an antibody-drug conjugate, the link between the antibody and the cytotoxic agent plays a critical role in development of the ADC. Further, the nature of the linker can significantly affect the potency, selectivity, and the pharmacokinetics of an antibody-drug conjugate.

A common feature of numerous linkers used to prepare antibody-drug conjugates is their hydrophobicity – or their inability to dissolve in water.

In most cases, the average drug-to-antibody ratio (DAR) or the number of drug molecules per antibody does not exceed 3-4 drug molecules per antibody molecule.  Attempts to increase the DAR have often failed.  This is especially the case when both the cytotoxic agent and the linker are hydrophobic. Other reasons may be caused due to aggregation of the antibody-drug conjugates, the loss of affinity for the target antigen, and/or rapid clearance from circulation.

Many of the problems seen with hydrophobic linkers can be overcome by sulfonate- or PEG-containing hydrophilic (aqueous-soluble) linkers which are characterized by high solubility in both organic and aqueous solutions.

The attachment of PEG-based linkers to proteins and other biomolecules decreases aggregation and increases solubility.

Furthermore, branched or multi-arm PEG linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher rations of DAR than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. This, in turn, results in the ability to deliver a higher concentration of cytotoxic drug into the target cells per antibody binding event.

BroadPharm, a leading customer-focused biotech company based in San Diego, California, manufactures and supplies high quality PEG Linkers and, in addition Click Chemistry reagents and advanced Bio-labeling reagents such as Dye Labeling and Biotin Labeling compounds, for clients worldwide.

Founded in 2009, BroadPharm takes our customer needs as our highest priority. The company has over 2,000 discrete, high purity PEG reagents in stock which can be shipped to our clients immediately.

Because each product is synthesized and purified using BroadPharm’s proprietary advanced technology and characterized by modern NMR and LC/MS, BroadPharm’s PEG products, unlike traditional PEGs, represent a specific, single chemical structure with high purity.

Broadpharm’s PEG products offer many advantages over traditional linkers such as high water solubility, reduced aggregation and low immunogenicity. These PEG reagents have been widely used in bioconjugation, the development of antibody-drug conjugates or ADCs, as well as therapeutic, drug delivery and diagnostics fields.

In addition, the company also offers IP-protected custom synthesis and bio-conjugation services for clients in the pharmaceutical and biotech industries. This includes providing timely technical support to address a client’s specific need and offer technical advice for the best use of the company’s new products.

With a strong background and expertise in modern chemistry, innovative and novel PEG technology and state-of-the-art equipment, BroadPharm helps customers to accelerate their research through cost-effective and efficient solutions.

Earlier this month, the team of ADC Review | Journal of Antibody-drug Conjugates asked David Zhang, Ph. D.,CEO, BroadPharm a few questions.

Q – Tell us a bit about the company.

Founded in 2009, BroadPharm has rapidly become a leading manufacturer and supplier of high quality PEGylation reagents, ADC linkers and Bio-labeling tools to the pharmaceutical and biotech industry worldwide. These reagents are manufactured using our innovative technology with strict QA/ QC standards to ensure that world-class reagents are supplied to the market. Hundreds of pharmaceutical and biotech companies, as well as academic institutes, are using our products.

Q – You’ve developed a series of ADC linkers with water soluble PEG spacer of various lengths to further empower antibody drug conjugates and other drugs development research. Tell us a bit about that.

We offer a series of PEGylated ADC linkers to our clients in ADC drug development such as Mal-PEG-Val-Cit-PAB-PNP and Azido-PEG-Val-Cit-PAB-PNP. Introduction of the PEG moiety to the ADC linker helps improve its aqueous solubility and optimizes its DMPK profile. BroadPharm also collaborates with our ADC drug development clients to design and synthesize new ADC linkers with or without PEG chains.

Beyond ADCs
PEG linkers are also applied in small molecules drug modifications as exemplified by NKTR-181, a novel drug and a first-in-class opioid analgesic as well as a new chemical entity (NCE) that is the first full mu-opioid agonist molecule designed to provide potent pain relief. The attachment of a short-chain PEG to a five-ring morphinan prevents the drug from crossing the blood-brain barrier and makes it a non-habit-forming drug and preventing drug abuse.

Last Editorial Review: June 22, 2018

Featured Image: San Diego Skyline from Coronado Island. BroadPharm is a leading customer-focused biotech company based in San Diego, California. Courtesy: © 2010 – 2018. © Fotolia 2017. Used with permission.

Copyright © 2018 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.


AACR 2017: Seattle Genetics Research on Novel PEGylated Glucuronide-MMAE Linker Technology for Next-Generation ADCs

With three Antibody Drug Conjugates (ADCs) currently on the market, and more than 40 in clinical trials, there is much interest in research and investment towards these rapidly growing, promising cancer treatments. This was clearly evident at this year’s American Association of Cancer Research (AACR) meeting held April 1 – 5 in Washington DC, where a large number of posters and oral sessions focused on the advancement and innovation of antibody-drug conjugates.

During the session “From Chemistry to the Clinic: Part 3: Advances in Antibody Drug Conjugates,” held Saturday, April 1, 2017,  Patrick J. Burke, PhD., Principal Scientist at Seattle Genetics presented the company’s development work towards increasing potency of ADCs with a monomethyl auristatin E (MMAE) payload through higher drug loading by use of a polyethylene glycol (PEG)ylated glucuronide linker system.

Today, the majority of antibody-drug conjugates in development include functionalities that are hydrophobic. This results in increased plasma clearance. As a result, there has been significant interest in generating new linkers that compensate for this potential liability.[1]

Burke detailed some of the difficulties with current  MMAE linker technologies, and how their lead PEGylated glucuronide-MMAE linker that uses a self-stabilizing maleimide and a PEG12 side chain is addressing these issues, potentially enabling highly potent and homogenous ADCs.

While the linker technology that has enabled antibody-drug conjugates like gemtuzumab ozogamicin (Mylotarg®; Pfizer), brentuximab vedotin (Adcentris®; Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), and  has been pivotal in establishing ADCs as viable treatment options, there are many limitations to these technologies.

The conjugation of the drug payload to residues like lysine and cytosine, for example, leads to a high degree of heterogeneity in the product. Additionally, these ADCs are hydrophobic in nature, and this hydrophobicity can have a negative impact on the pKa of the conjugates, resulting in limited number of drugs per antibody, which is often capped at a drug-to-antibody ratio of 4 (DAR4) or less. There is also a limited set of chemical functions with the groups that are currently being used to attach a cleavable type of linker system. [2]

PEGylated glucuronide-MMAE linker
Burke described three ongoing projects at Seattle Genetics designed to solve these issues, most notable of which was their efforts to increase ADC potency with the PEGylated glucuronide-MMAE linker system that can enable a higher DAR. With current vcMMAE ADCs, conjugating more copies of vcMMAE to an antibody is more potent in vitro, but the results are not the same in vivo, where higher loaded conjugates are cleared more rapidly. With this new linker system, it is possible to harness more potency as well as create more homogenous ADCs in vivo.

To accomplish this, the glucuronide-MMAE linker system incorporates a carboxylic acid trinol motif that makes it more hydrophilic. Alone, this linker isn’t enough to make DAR8 ADCs, which is why Seattle Genetics has incorporated a PEG polymer. The PEG was incorporated in a side chain configuration was found to be ideal, and different PEG sizes (2, 8, 12, and 24) were tested for any changes in efficiency.

Burke presented these data comparing PEGylated and non-PEGylated constructs as well as PEG size efficacy. As expected, the constructs that lacked PEG cleared most rapidly and severely decreased exposure, while an increase in exposure was seen in a stepwise fashion up until a PEG of 8. In tolerability studies with the same constructs at a dose of 15mg/kg, only animal groups that were given PEG sizes sufficient to preserve the pharmacokinetics (PK) properties of the conjugates survived, whereas survival was not seen in animals dosed with insufficient PEG.

Importantly, this linker was then compared to vcMMAE in an experiment looking at a CD90+ model. This data shows that when both constructs were loaded with their ideal DAR (4 for vcMMAE and 8 for the PEGylated glucuronide-MMAE linker), animals treated with 3mg/kg of vcMMAE saw a brief tumor delay, while those given PEGylated glucuronide –MMAE conjugate at the same dose saw a complete remission. When the glucuronide-MMAE linker was given at lower dose of 1mg/kg, the results were similar to the 3mg/kg of vcMMAE, leading to the conclusion that PEGylated glucuronide –MMAE conjugates show a three-fold potency increase when compared to vcMMAE. [3]

Previous work
This presentation confirmed previous work presented during the 2014 annual meeting of the AACR. Work presented at this meeting demonstrated that incorporation of a discrete PEG24 polymer into the cleavable β-glucuronide-MMAE linker system either increased or decreased the plasma clearance of the resulting antibody-drug conjugate. This result depended on the configuration of the PEG. For example, when inserted into the drug-linker as a stretcher unit between the maleimide and the cleavage site, PEG24 elicited increased ADC plasma clearance. In contrast, incorporation of the PEG24 as a side chain from a modified lysine residue adjacent to the maleimide resulted in ADCs with slower clearance.

Moving forward, a PEG of up to 12 with this side chain configuration has proven to be ideal for SGNC48A, an ADC that is targeted toward CD48, and which is expected to go from preclinical to Phase I clinical trials this year. Since CD48 is present on 90% of multiple myeloma cancer cells, this technology has the potential to make a huge impact in this difficult to treat patient population. Clinical trials on SGNC48A will be updated in our ADC drug map as progress goes on.

Last Editorial Review: May 19, 2017

Featured Image: Capitol Building, Washington, DC.Courtesy: © 2017 Fotolia. Used with permission.

Copyright © 2017 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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