Avacta Life Sciences, the developer of Affimer® biotherapeutics and research reagents will collaborate with Glythera a developer of advanced, stable conjugation chemistries and novel, ultra-potent toxin payloads, to evaluate the use of the Avacta’s Affimer® technology in combination with Glythera’s PermaLink™ conjugation chemistry. The partners announced that the ultimate goal is to develop a new class of of highly targeted bio-therapeutics which may have the potential to be a superior alternative to antibody-drug conjugates or ADCs.

Today two ADCs are approved by regulators in the United States and Europe and more than 50 are currently in clinical development. Approximately a quarter of the investigational agents are in phase II or Phase III trials. [1] Analysts estimate the market to be worth around US $ 1 billion today from two approved antibody-drug conjugates. They expected it to be worth US $ 10 billion annually by 2024.

The combination of the two companies’ technologies has the potential to deliver … best-in-class solutions…  opening additional avenues for bringing novel therapeutic to market… which could lead to … improved patient outcomes…

Increased therapeutic activity
Antibody-drug conjugates are highly potent biologics composed of a tumor specific monoclonal antibody linked via a linker to a cytotoxic drug.  By combining the unique targeting ability of monoclonal antibodies to discriminate between normal, healthy tissue and cancer cells, they are able to considerably reduce damage to healthy, normal tissues.

ADCs are being developed with the goal of increasing, and achieve, increased therapeutic efficacy by delivering highly potent cytotoxic molecules (with the cancer-killing ability of highly potent cytotoxic drugs with cellular IC50 values in the pM range).

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Critical aspects in the development of successful ADCs include the selection of the targeting antigen, the monoclonal antibody against the target, the cytotoxic molecule or payload, the linker bridging the cytotoxic molecule and the antibody, and, finally, the conjugation chemistry.

Linker technology
Linkers are small organic chemical moieties or peptide of several amino acids required for the specific attachment of a highly potent cytotoxic payload to the antibody. Stable linkers play a crucial role in antibody-drug conjugates, and linker properties greatly influence the ADC’s pharmacokinetics, therapeutic index and efficacy.  The ideal linker is systemically stable so that biophysiochemcial property of the antibody-drug conjugate are similar to that of the unconjugated antibody. At the same time, linkers should still be able to release the payload at the target site. [2][3]

Despite key advances made in linker chemistries, off-target toxicities, toxicities other than in cancer cells, are reported in several ADCs in clinical development. Off-target toxicities me be caused as a result of the limited stability of chemical linkages between antibody and cytotoxin, resulting in the the payload coming off the antibody and causing off-target toxicity and often severe, side effects.

This remains as a challenge, creating a need to improve linker chemistries.

Scientists are conducting extensive research to develop novel linkers utilizing linker platforms that include both cleavable and non-cleavable linkers. Linker technology is also crucial for improving the therapeutic window of an antibody-drug conjugates.[3]

Scaffolding technology
The collaboration between Avacta and Glythera aims to develop technologies that have the potential to create an analogous leading protein drug conjugate platform with a number of benefits over current ADC offerings.

Avacta’s Affimer technology is based on the cystatin protein fold. It has high affinity and high specificity. Affimer reagents are selected from libraries in which 12 – 36 amino acids are diversified giving a predicted total binding surface area of 650-1000 Å2. Unlike antibodies, Affimer reagents and biotherapeutics are produced in vitro.[4]

The reagents contain no disulphide bonds, are expressed easily in E. coli and have no batch to batch variability. One of the unique characteristics is that they can distinguish between proteins that differ by only a single amino acid.  Furthermore, they can be generated against targets which are intractable for antibodies and can even detect whether a protein is in an active or inactive conformation.[4]

Being proteins Affimer reagents don’t have the problems associated with aptamers, a special class of small RNA/DNA molecules which can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets and essentially a chemical equivalent of antibodies.[4][5]

The Affimer scaffold has been engineered so that it does not binds to proteins found in human cells, serum or plasma. As a result,  interaction with an Affimer molecules are specifically defined by the engineered peptide loops made up of 19 naturally occurring amino acid side chains.[4]

The technology offers scientists the ability to closely control the position and number of cytotoxins in the payload. One of the benefits is that the technology has much shorter development times, allows for flexibility to “design-in” the required pharmacokinetics (i.e. the time the drug spends in the blood stream), and is much easier, more consistent and has lower cost production. The small size of the Affimer molecule is likely to also improve tumour penetration compared with antibodies which are ten times larger in size.

Exceptionally stable
PermaLink is Glythera’s highly specific proprietary cysteine linker technology that generates exceptionally stable antibody-drug conjugates with enhanced selectivity and specificity. Efficacy was demonstrated in both in vitro and in vivo for trastuzumab/monomethyl auristatin E (MMAE) based ADCs using various accepted cancer cell line models.  These studies demonstrates that the direct substitution of maleimide for an alternative conjugation technology has resulted in enhanced anti-cancer activity in a xenograft model,  providing a more stable attachment of the cytotoxic payload.  These studies further show that efficacy outperforms maleimide-based linkers in a mouse xenograft models. This approach can  potentially reduce off-target toxicity effects.[6]

PermaLink is highly specific for the sulfhydryl groups of cysteine residues which are a primary site for cytotoxic drug attachment in many antibody-drug conjugates currently in clinical development
The novel technology enhances stability provided by a stable thioether bond which is resistant to biological and chemical degradation. Furthermore, because PermaLink can be tailored to generate both “non-cleavable” and “cleavable” linkers for efficient release of active drug following antigen-mediated internalization, the technology is compatible with a diverse range of cytotoxic payloads. [6]

Under the terms of the agreement, the companies will develop materials and methods to be used in the generation of Affimer-drug conjugates. The proof of concept study aims to demonstrate the key technical and commercial benefits of the combination over traditional antibody and linker approaches. The two companies will partner to offer Affimer-drug conjugate development services, and licensing of the combined platform, to pharmaceutical developers.

“We set out a detailed commercial strategy for Affimer technology, and [our new] collaboration with Glythera in the area of ADCs is another important application area,” Alastair Smith, Chief Executive Officer of Avacta, said.

“The combination of the two companies’ technologies has the potential to deliver a best-in-class solution. We’re  confident that the partnership will demonstrate the utility of the Affimer platform as a powerful approach to generating a broad range of biotherapeutics, creating opportunities for third party licensing of the platform with the potential to generate long-term value for both companies,” Smith noted.

“[I expect that] combining PermaLink conjugation chemistry with the Affimer technology will demonstrate the benefits of PermaLink across a new targeting molecule class, opening additional avenues for bringing novel therapeutic to market.  [I think that] the is a step forward in bio-therapeutic development which could lead to[novel agents] and improved patient outcomes,” Dave Simpson, Chief Executive Officer of Glythera added.

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