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.

Lonza
Broadpharm
ADC Bio
MabPlex
 

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]