Using its proprietary REsidue-SPEcific Conjugation Technology™, also known as  RESPECT™, combined with the company’s eribulin-linker toxin platforms, Morphotek, a subsidiary of Eisai, confirmed the launch of  its antibody-drug conjugate (ADC) Services business.

Morphotek’s RESPECT™ is a site-specific conjugation technology that targets select amino acid residues as a way of producing investigational homogeneous antibody-drug conjugates or ADCs with defined drug-to-antibody ratios or DARs.

The platform allows two methods by which payloads can be conjugated to specific residues in an antibody: a site-specific conjugation of a single cytotoxic payload or two payloads with different mechanisms of action.

Cysteine-specific conjugation
The RESPECT technology includes a cysteine-specific conjugation method which exploits a unique intra-chain disulfide bond in the light chain of oryctolagus cuniculus-derived antibodies between residues 80 and 171 of the variable and constant domains, respectively.  Morphotek’s humanization strategy allows retention of the cysteine at position 80 with a free thiol group that is both amenable for residue-specific conjugation and compatible with optimal antibody biophysical properties, including antigen binding and structural stability. [1]

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The RESPECT platform has been optimized via antibody engineering using in-silico modeling, extensive mutagenesis and crystallographic studies that have defined optimal adjacent residues to the retention of a reactive thiol group, as well as the desired humanized antibody’s properties.

Lysine-specific linkage
Morphotek’s C-terminal lysine-specific linkage method employs the transglutaminase enzyme that catalyzes the formation of a stable isopeptide bond between the γ-carboxyamide group (acyl donor) of a glutamine and the ε-amino group (acyl acceptor) of a lysine.

Morphotek’s scientists explained note that no acyl acceptor sites are present in recombinant wild-type IgG, monoclonal antibodies lack the C-terminal Lys447 due to cleavage by carboxypeptidase B in the host production cell line. They also noted that blocking the cleavage of Lys447 by addition of a C-terminal amino acid results in transamidation of Lys447 by a variety of acyl donor substrates in the presence of non-acidic, non-proline amino acid residue at position 448. [1]

Morphotek’s conjugation technologies allow targeting specific amino acid residues as a way to produce a homogeneous ADCs with a defined drug-to-antibody ratio

Figure 1.0: AACR 2017 Poster 65 | RESPECT (REsidue-SPEcific Conjugation Technology): A Platform Technology Utilizing Native Cysteine and Lysine Residues for the Generation of Homogeneous Antibody-Drug Conjugates. [1]
Erbulin platform
The platform employs eribulin mesylate (Halaven®) an FDA-approved drug, as one of the cytotoxic payloads. Eribulin mesylate, a microtubule-destabilizing agent, is a synthetic analogue of halichondrin B, isolated from the marine sponge ‘Halicondria Okaida.’ In large phase III clinical trials the unconjugated drug has resulted in prolonging overall survival of heavily pretreated metastatic breast cancer patients.[2]

Eribulin is used along with a proprietary high-throughput screening system that can evaluate multiple ADC products simultaneously for client-desired biophysical properties and target-specific binding. As part of the company’s services, the eribulin-linker payload is offered as an option to develop investigational ADCs using traditional bioconjugation for companies interested in developing next-generation formats of their own antibodies.

“Decades of expertise in antibody engineering and clinical development of biologics-based therapies, along with pre-clinical studies showing the potential of our new ADC formats, has enabled us to align these assets into a client-focused ADC business offering end-to-end services,” said Nicholas Nicolaides, President and CEO of Morphotek.

Increasing value
“We believe this new service provides an opportunity to build a win-win strategy by increasing internal value through leveraging our proprietary platforms and development know-how, and customer value by developing ADCs to their strategic targets,” Nicolaides added.

Large-scale purification
Morphotek’s end-to-end ADC services business allows for multiple entry points for clients, starting from development of a site-specific bioconjugate-ready monoclonal antibody and ADC to in vivo safety and efficacy validation.

Additional options include manufacture of GMP clinical trial material, GLP toxicology studies and/or development of IHC companion diagnostics for patient screening.

As part of their manufacturing process, scientists at Morphotek have developed a robust process for the large-scale purification of conjugatable humanized rabbit antibodies that can be adapted to a manufacturing process.

AACR 2017
This year, during Annual Meeting of the American Association for Cancer Research (AACR) in Washington, D.C. being held April 1-5, 2017, scientists from Morphotek present a posters highlighting pre-clinical data on on the company’s proprietary RESPECT technology. [3]

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