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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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Eisai’s Subsidiary Morphotek Launches ADC Services

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]

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]


Last Editorial Review: April 3, 2017

Featured Image: Front view of the Capitol Building in Washington DC, USA from in front of the entrance staircase under bright blue sky. 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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