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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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ADC Therapeutics Ends ADCT-502 Development Program

Earlier this week Lausanne, Switzerland-based ADC Therapeutics, an oncology drug discovery and development company specializing in the development of proprietary antibody-drug conjugates or ADCs designed to target major hematological malignancies and solid tumors, confirmed that the company has terminated its Phase I clinical trial program for ADCT-502 in patients with advanced solid tumors with HER2 expression.[1]

ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with a novel class of highly potent cytotoxic agents linked via a chemical linker.

Figure 1.0: Study evaluates ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression. Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1. This is the first clinical study with ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression.

The investigational agent, targeting HER2 expressing solid tumors, did, based on data on safety, tolerability, pharmacokinetics and efficacy, not demonstrate sufficient patient benefit to justify further development.

While the single group assessment trial was planned to have two parts, the expected risk/benefit ratio had not been achieved by the end of part one.

In total, the study enrolled not more than 20 patients (278 were planned) with solid cancers, including breast cancer, non-small cell lung cancer, gastroesophageal, and bladder cancer.

In the first part of the trial, researchers tested the safety and tolerability of ascending ADCT-502 doses. Unfortunately, the initial results showed that anti-cancer responses were only seen at higher doses. These higher doses were not well-tolerated by patients. As a result, the trial failed to achieve its primary objective and was suspended.

PBD-based ADC programs
“We are very pleased with the efficacy and tolerability achieved with our lead hematological PBD-based ADC programs, but regrettably this has not been the case with our HER2 targeted ADC,” said Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics,

Pyrrolobenzodiazepine dimers or PBD’s are extremely potent and have a well characterized safety profile that includes fluid retention and pulmonary edema. For most PBD-based ADCs this can be managed by selecting dosing regimens that are efficacious with manageable toxicities.

“However, during dose escalation in this trial we did not achieve the necessary efficacy at tolerated doses required for patient benefit. This was possibly due to the extensive expression of HER2 in pulmonary tissue,” Feingold explained.

Photo 1.0: ADC Therapeutic at the 2017 annual meeting of the American Society of Hematology in Atlanta, GA.

“Our next two solid tumor ADCs progressing into the clinic over the next nine months incorporate site specific conjugation technology which based on pre-clinical models has the potential to substantially improve tolerability and efficacy in difficult to treat solid tumors. Preclinical data on these programs was presented at the recent American Association of Cancer Research conference,” he added.

“Patients with HER2 expressing tumors have multiple therapeutic options including novel therapies in clinical development that are producing encouraging data. ADC Therapeutic’s strategy is to progress a deep pipeline of ADCs into Phase I in order to assess their clinical and market potential based on actual human data, and only to progress into later stage development those ADCs that demonstrate the potential to be best in class in areas of high unmet medical need.We currently have three other ADC programs in the clinic, and we plan to commence clinical trials for three additional programs in the next 9 months, including a third hematological program,” Chris Martin, CEO at ADC Therapeutics said.

“Moreover, our two most advanced clinical programs are progressing into later stage development over 2018,” he added,

At this time, ADC Therapeutics is collecting and evaluating the study data from the ADCT-502 Phase I-trial, which will be presented for publication later this year.


Last Editorial Review: April 26, 2018

Featured Image: Clinical research Courtesy: © 2018. Fotolia. Used with permission. Photo 1.0: ADC Therapeutic at the 2017 annual meeting of the American Society of Hematology in Atlanta, GA. Courtesy: © 2018. Sunvalley Communication / Evan Wendt. Used with permission.

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Interim Data Shows Favorable Tolerability and Efficacy Results of ADCT-301 in Extensively Pretreated Lymphoma Patients

Interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, being developed by ADC Therapeutics for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirms  favorable tolerability and efficacy. [1]

The results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL).

Lymphoma is a cancer that begins in cells of the immune system, in particular in the lymph system. The lymph is rich in lymphocytes, a type of white blood cells that help the body fight off infections and other diseases. Lymphoma develops when lymphocytes become cancerous which can occur in both children and adults.

The two main types of lymphomas are Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL), and are differentiated by the type of lymphocytes affected and their appearance under the microscope.

According to the National Cancer Institute around 72,000 new people are diagnosed with non-Hodgkin lymphoma in the United States and around 9’000 new people are diagnosed with Hodgkin lymphoma.

Trial results
The results included data from 37 extensively pretreated patients with a median age of 46 years, a median treatment duration of 43 days and 2 treatment cycles. Among all patients enrolled at the time of the data cutoff for presentation and evaluable for safety, the most common treatment emergent adverse events have been related to skin and decreased blood counts.

The overall response rate for evaluable patients with HL treated with doses 30μg/kg was 38.5% while 8 of 25 (32%) efficacy evaluable patients at all dose levels with HL and NHL have achieved stable disease as their best response. The researchers confirmed that ADCT-301 was well tolerated and toxicities manageable. Dose escalation continues.

Pyrrolobenzodiazepine-based ADC
ADCT- 301 is a novel antibody-drug conjugate (ADC) composed of HuMax®-TAC (licensed from Genmab), a monoclonal antibody directed against CD25 conjugated to ADC Therapeutics’ highly potent proprietary pyrrolobenzodiazepine (PBD)-dimer toxin. Once bound to a CD25-expresing cell, ADCT-301 is internalized into the cell where enzymes release the PBD- based payload.

CD25 is expressed in a wide range of hematological malignancies, including certain forms of lymphomas and leukemias, while its expression in healthy organs is restricted. This makes CD25, as a target, attractive.

“The results seen in this early analysis are impressive for these patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma have been heavily pre-treated,’ noted Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“These data, combined with the positive results we have seen in preclinical studies continue to highlight what we believe to be the significant potential of our ADC technology platform based on PBD-warheads,” Feingold added.

“Patients with multiply relapsed or refractory Hodgkin’s or non-Hodgkin’s lymphoma have limited treatment options. These early findings are very encouraging as they demonstrate a clear clinical benefit even at low doses for patients who failed, or are intolerant to any established therapy,” explained principal investigator Steven M. Horwitz, Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York City.

“We look forward to continuing this study to further identify the maximum tolerable dose of ADCT-301 and provide a preliminary assessment of its single-agent anti-tumor activity and toxicity profile,” Horwitz added.

In addition to the ongoing Phase I trial, ADCT-301 is currently being evaluated in an ongoing Phase I clinical trial in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). ADC Therapeutics has four PBD- based antibody drug conjugates in six ongoing Phase I clinical trials in the USA and in Europe.


Last editorial review: June 16, 2017

Featured Image: Lugano, Switzerland.Courtesy: © 2017 Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland Used with permission.

Copyright © 2017 InPress Media Group, LLC. 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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First Patient with Advanced Solid Tumors with HER2 Expression Dosed in a Phase I Clinical Trial of ADCT-502

A first patient with advanced solid tumors with HER2 Expression was dosed in a phase I clinical trial with ADCT-502. The investigational drug being developed by ADC Therapeutics represents the company’s fourth proprietary Antibody-drug Conjugates (ADCs) programs in clinical six clinical trials and is designed to evaluate and provide data on safety, tolerability, pharmacokinetics and efficacy.

The clinical trial is a two stage, open-label Phase Ia/Ib clinical trial. The first stage (Phase Ia) is a dose escalation phase which will recruit patients at leading clinical centers across the United States and and Europe, and will seek to determine the recommended dose of ADCT-502. The second consecutive stage (Phase Ib), has the objective to confirm the safety and efficacy profile for ADCT-502 in expanded patient cohorts in multiple potential cancer indications.

Investigational agent
ADCT-502 combines a humanized monoclonal antibody trastuzumab targeting the human epidermal growth factor receptor 2 (HER2) with a pyrrolobenzodiazepine (PBD-based) linker-drug tesirine payload. Tesirine, a cathepsin B-cleavable valine-alanine PBD payload also known as SG3249, has been designed to combine potent anti-tumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. It is a potent and clinically validated PBD payload currently being employed in the clinic in a number of ADCs, including the CD25-targeted ADCT-301, the CD19-targeted ADCT-402, both for the treatment of lymphoma and leukemia, and the DDL3-targeted rovalpituzumab tesirine for the treatment of small cell lung cancer.

The antibody is site-specifically conjugated to the payload. Once bound to the HER2 receptor on the cell surface, ADCT-502 is internalized into the cell where enzymes release the PBD-based payload.The HER2 surface protein is expressed at high or low levels in a variety of different tumor types, including breast cancer, gastric and gastroesophageal cancers. It is also a well-established, clinically validated target.


Figure 1.0: Pyrrolobenzodiazepine dimers are an emerging class of payloads used in antibody-drug conjugates (ADCs). Tesirine also known as SG3249, is a N10 linked PBD dimer designed to combine potent anti-tumor activity with desirable physicochemical properties, including favorable hydrophobicity and improved conjugation characteristics.

Clinical studies
Preclinical data presented during the 2017 annual meeting of the American Association for Cancer Research (AACR) shows superior in vivo anti-tumor activity of ADCT-502 compared to T-DM1 (ado-trastuzumab emtansine/Kadcyla®; Genentech/Roche) in various tumor xenografts with low HER2 levels.  These results support the development of ADCT-502 not only in patients that have become resistant/refractory to T-DM1, but also in patients whose tumors express low levels of HER2, and are not eligible for treatment with T-DM1. [1]

Overall, the ADCT-502 has exhibited strong dose-dependent anti-tumor activity at low single doses against both low and high HER2 expressing tumors. Given the substantial prevalence of HER2 expression in a range of cancers, ADCT-502 will be evaluated in patients with non-small cell lung cancer (NSCLC), bladder, biliary tract, and ovarian cancer, for which HER2 targeted therapies are not yet approved.

“This is the fourth ADC we have put into the clinic in just over two years. Dosing the first patient in this trial with ADCT-502 is an important milestone for us and could pave the way for a better treatment regimen for patients,”  said Jay M. Feingold, MD, Ph.D. , Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“The trial will give us vital data on safety, tolerability and dosing. Our preclinical studies suggest ADCT-502 may provide significant clinical benefit for patients suffering from a variety of tumor types which are known to express HER2 in a significant proportion of patients. We are exploring this potential in lung, bladder and biliary tract cancers further within this study as well as in the more established indications of breast and gastric cancer,” Feingold added.

Eagerly expected
“Tremendous advances have been made in the treatment of HER2 expressing cancers, particularly gastroesophageal and breast cancers, in the past 20 years,” noted Kyriakos P. Papadopoulos, MD, Senior Clinical Investigator of the START Center for Cancer Care in San Antonio, Texas,  and one of the investigators of the study.

“However, a significant portion of this patient population still fail to respond or relapse with currently available therapies. Having seen the effects of other pyrrolobenzodiazepine ADCs in various tumor types in recent years, we eagerly anticipate the results of this study,” Papadopoulos concluded.


Last Editorial Review: May 19, 2017

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Successful Funding Round Expected to Accelerate ADC Therapeutics’ Clinical Development

Swiss Biotech company ADC Therapeutics, an oncology drug discovery and development company specializing in the development of proprietary antibody-drug conjugates or ADCs for the treatment of both solid and hematological cancers, has raised US $ 105 million (€ 97 million) through a private placement. The financing was oversubscribed and supported by both new and existing investors, including the company’s founder, Auven Therapeutics, a private equity firm pursuing an innovative life science investment strategy, the Wild Family Office and AstraZeneca.  The investment represents the largest funding round of 2016 in Europe.

Since inception in 2012, the Company has raised $255 million to advance its pipeline of proprietary ADCs.


This financing [round] acknowledges the progress ADC Therapeutics has made with its pipeline of clinical and preclinical programs in areas of high unmet medical need…


ADC Therapeutics’ highly targeted biopharmaceutical drugs combine monoclonal antibodies specific to surface antigens present on particular tumor cells with a novel class of highly potent pyrrolobenzodiazepine (PBD)-based payload via a chemical linker.

The company’s pyrrolobenzodiazepines (PBD)-based cytotoxins or “payloads” do not distort the structure of the target cell’s DNA, its antibody-drug conjugates offer the prospect of highly potent, target-selective cancer therapies with fewer side effects and the potential to pre-empt resistance issues faced by classical, existing, anti-cancer products on the market. ADC Therapeutics has an exclusive license from Spirogen, a subsidiary of MedImmune, the global biologics research and development arm of AstraZeneca, for its PBD chemistry platform for use in a number of proprietary programs.

Accelerate clinical development
The financing proceeds will be used to accelerate the progress of ADC Therapeutics’ pipeline in clinical development, and to fund commercial manufacturing processes for its lead programs. The company’s first two programs, ADCT-301 and ADCT-402, are currently in four clinical studies in important sub-types of lymphoma and leukemia.  The company’s management team anticipates its next two pipeline programs, both targeting solid tumour cancers, will commence clinical development later in 2016 and early in 2017, respectively.  As part of their accelerated clinical development program, ADC Therapeutics expects to have a total of six programs in clinical development within 18 months.

“This financing acknowledges the progress ADC Therapeutics has made with its pipeline of clinical and preclinical programs in areas of high unmet medical need,” noted Chris Martin, Ph.D, the CEO of ADC Therapeutics.

“We are now extremely well positioned to support our lead programs through multiple expansion studies based on the efficacy signals that are emerging from our initial clinical trials. We continue to rapidly grow our pipeline of proprietary antibody-drug conjugates in important hematological and solid tumor indications both on our own and in partnerships,” Martin noted.

Partnerships
ADC Therapeutics, based in Lausanne, Switzerland and has operations in London, San Francisco and New Jersey,  enjoys strong relationships with a number of world class partners, including Astrazeneca and its global biologics research and development arm, MedImmune, Genmab and Cancer Research Technology.


Last Editorial Review: October 19, 2016

Featured Image: Laboratory glass. Courtesy: © Fotolia. Used with permission.

Copyright © 2016 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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Cancer Research Technology, University of Copenhagen and ADC Therapeutics Sign Agreement

Cancer Research Technology UK and the University of Copenhagen announced their agreement with Switzerland-based ADC-Therapeutics SA  to develop novel antibody therapeutics for the treatment of cancer.

The University of Copenhagen agreed with ADC Therapeutics to license antibodies against a cancer-specific cell surface protein. The antibodies will be used by ADC-Therapeutics to develop a novel antibody-drug conjugate or ADC that could potentially treat a range of cancers.

The antibodies – jointly developed by scientists from Cancer Research UK and the University of Copenhagen – target a protein overexpressed on the surface of some cancer cells, which is not expressed on healthy cells.

ADC-Therapeutics intends to incorporate the antibodies into a novel antibody-drug conjugate using its proprietary linker and pyrrolobenzodiazepine (PBD) cytotoxic warhead technology. The antibodies are expected to selectively target the PBD cytotoxic to cancer cells, sparing normal tissue. [1]

Pyrrolobenzodiazepines are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. They are significantly more potent than systemic chemotherapeutic drugs. Novel results demonstrate that PBDs can be effectively used for antibody-targeted therapy.[1]

New cancer treatments
“We are very pleased and proud that research from the University’s Faculty of Health and Medical Sciences has been licensed to ADC-Therapeutics for the development of new cancer therapeutics,” noted Thomas Bjørnholm, Pro-Vice-chancellor for Research and Innovation, the University of Copenhagen.

“Our mission as a public university is precisely to make sure that our leading-edge research is disseminated and is taken to the market together with commercial partners for the benefit of society at large,” Bjørnholm continued.

“This important license deal brings together CRT’s access to world class research and ADCT’s cutting edge technology to develop exciting new therapeutics for cancer,” added Keith Blundy, Ph.D, Cancer Research Technology’s chief executive.

“We hope this agreement will pave the way for promising new ways to treat a range of cancers in a targeted way without damaging healthy tissue,” Blundy concluded.


Last Editorial Review: April 23, 2016

Featured Image: Life scientist researching in the laboratory.. Courtesy: © Fotolia Photo. Used with permission.

Copyright © 2016 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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First Patient Dosed in Phase I Trial of ADCT-402 in CD-19 Positive B-cell Non-Hodgkin Lymphomas

Late last week, Swiss based ADC Therapeutics, an oncology drug development company that specializes in the development of proprietary antibody-drug conjugates (ADCs) targeting major solid and hematological cancers, confirmed that the first patient has been dosed in a Phase I trial to evaluate its antibody-drug conjugate (ADC) ADCT-402 in B-cell non-Hodgkin Lymphoma (B-NHL).

The two stage, open-label trial will evaluate the tolerability, safety, pharmacokinetics and activity of ADCT-402 in patients with relapsed or refractory B-NHL. The first stage is a dose escalation phase which will recruit up to 30 patients at ten clinical sites across the US and EU and will seek to determine the recommended dose of ADCT-402 for the second stage. The second stage, which will begin once an appropriate dose is identified, aims to confirm the safety and efficacy profile at the selected dose.

Attractive target
ADCT-402 combines a humanized monoclonal antibody targeting the protein CD19 with a pyrrolobenzodiazepine (PBD) payload. CD19 is a B-cell specific surface protein expressed throughout B-cell development. It is expressed on nearly all B-cell malignancies in many non-Hodgkin lymphomas. Due to its specificity, it has become an attractive target for ADC therapies. In preclinical in vivo models, ADCT-402 exhibited strong dose-dependent anti-tumor activity against CD19-positive leukemic and lymphoma cell lines at low single doses, and it outperformed other CD19 targeted ADCs currently in clinical development.

B-cell non-Hodgkin Lymphoma is a common type of non-Hodgkin lymphoma, a cancer of the lymphatic system. Non-Hodgkin Lymphomas overall are the 10th most common cancer in the world. In 2012, there were nearly 386,000 new cases diagnosed globally, with highest incidence rates reported in Northern America.

“Dosing the first patient in this trial with ADCT-402 is an important milestone for us and could pave the way for a better treatment regimen for patients. The trial will give us vital data on safety, tolerability, dosing and efficacy over the next two years,” noted Jay Feingold, MD, the Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“Following our preclinical studies suggesting ADCT-402 may also provide significant clinical benefit for patients suffering from lymphoblastic leukemia, we are exploring this potential further with a second study in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia now also open for patient recruitment,” Feingold continued.

Advancing treatments
“Tremendous advances have been made in the treatment of non-Hodgkin Lymphoma in the past 20 years. However, a significant portion of the patient population still fail to respond to currently available therapies. Having seen the effects of other ADCs in various tumour types in recent years, we eagerly anticipate the results of this study,”  explained Owen O’Connor, MD, Principal Investigator for the study and Professor of Medicine and Experimental Therapeutics, and the Director of the Center for Lymphoid Malignancies at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center,

Additional therapies
ADC Therapeutics currently has two PBD-based ADCs in four clinical trials, with a deep pipeline of other ADCs in preclinical development. The company’s ADCT-301 and ADCT-402 programs entered Phase I clinical development for lymphoma and leukemia in 2015.


Last Editorial Review: March 11, 2016

Featured Image: Microscope. Courtesy: © Fotolia Photo. Used with permission.

Copyright © 2016 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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First Patient Dosed in Phase I Trial of ADCT-301 Trial

Earlier this month ADC Therapeutics, a Swiss-based oncology drug development company, dosed the first patient in a Phase I trial to evaluate ADCT-301, also know as HuMax®-TAC-ADC, its lead antibody-drug conjugate or ADC for the treatment of patients with Acute Myeloid Leukemia (AML). The drug, which has the potential to be a first-in-class ADC is in development for lymphoma under an agreement between Genmab and ADC Therapeutics.

The two stage, Phase I open-label trial will evaluate the tolerability, safety, pharmacokinetics and activity of ADCT-301 in patients with relapsed or refractory CD-25 positive AML. CD25 is expressed on a variety of hematological tumors and shows limited expression on normal tissues, This makes it a very attractive target for antibody-payload approaches.

The initial dose escalation phase will recruit up to 30 patients at ten clinical sites across the US and will seek to determine the recommended dose of ADCT-301 for the second stage. The second stage, which will begin once an appropriate dose is identified, will be expanded into the UK and Europe with the recruitment of up to 30 additional patients.

Strong dose-dependent anti-tumor activity
ADCT-301 is composed of Genmab’s HuMax®-TAC, a monoclonal antibody directed against CD25 (the alpha chain of the IL-2 receptor) conjugated to ADCT’s highly potent proprietary pyrrolobenzodiazepine / PBD-dimer using ADC Therapeutics proprietary linker technology. In preclinical in vivo models, ADCT-301 exhibited strong dose-dependent anti-tumor activity against CD25-positive cell lines at single low doses.

“Acute myeloid leukemia is the most common leukemia in the adult population in United States and the prognosis is poor. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis,” explained Professor Martin Tallman, the Principle Investigator of the trial and Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center, New York. ADCT-301 has shown promise in in vivo studies and we believe that this important trial could help us to improve patient outcomes.”

“Dosing the first patient in this trial with ADCT-301 is an important milestone for the Company. We look forward to the progress of this trial over the coming year and to accelerating the clinical development of our ADC pipeline,” added Chris Martin, MD, the Chief Executive Officer of ADC Therapeutics.

ADC Therapeutics currently has two PBD-based ADCs in four clinical trials, with four other ADCs in late preclinical development and further ADCs in research.


Last Editorial Review: February 10, 2016

Featured Image: Microscope. Courtesy: © Fotolia. Used with permission.

Copyright © 2016 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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ADC Therapeutics Raises US$ 80 million to Advance ADC Pipeline

ADC Therapeutics, an oncology drug discovery and development company headquartered in Lausanne, Switzerland and London, UK, that specializes in the development of proprietary Antibody Drug Conjugates (ADCs) targeting major cancers, has raised $80 million through a private placement of equity. New investors include leading European and US-based investors alongside founding investor Auven Therapeutics and participation from AstraZeneca.

The proceeds will be used to progress ADC Therapeutics’ product portfolio. The development pipeline includes the company’s lead program, ADCT-301, for the treatment of relapsed/refractory Non-Hodgkin or Hodgkin lymphoma, which entered Phase I clinical trials (NCT02432235) earlier this year.  The proceeds will also benefit the collaboration to develop up to two ADCs for commercialization with MedImmune, the global biologics research and development arm of AstraZeneca.

The antibody-drug conjugates being developed by ADC Therapeutics are highly targeted drug constructs which combine monoclonal antibodies (mAbs) specific to surface antigens on particular tumor cells with highly potent pyrrolobenzodiazepine (PBD)-based warheads. The company anticipates having seven drug candidates in human clinical trials in 2017.

ADCT-301
ADCT-301, the company’s lead program, is an antibody-drug conjugate composed of a recombinant human IgG1, HuMax®-TAC against human CD25 attached to a PBD warhead. [1]

The Interleukin-2 receptor-α (IL2R-α, CD25) is one of a heterotrimer making up the IL2R. It plays a major role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection. [1]  Based on the preponderance of CD25+ cells in hematological malignancies as well as the relationship between increased CD25 expression and poor prognosis, researchers became interested in investigating the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these specific cells in patients. The clinical proof of concept for treatment of CD25-positive malignancies was established using radio-immunoconjugates and immunotoxins with antibodies basiliximab, a chimeric mouse-human monoclonal antibody to the α chain (CD25) of the IL-2 receptor of T cells, and the humanized monoclonal antibody daclizumab[2][3]

During the 56th Annual Meeting of the American Society of Hematology (ASH) in December 2014, investigators reported that ADCT-301 demonstrated dose-dependent in vivo antitumor activity against SUDHL1 and Karpas 299 xenograft and disseminated models. The investigators showed that the trial drug, at a single dose of 0.2 mg/kg, significantly delayed Karpas 299 tumor growth compared to vehicle-treated and isotype control ADC-treated mice, and at 0.4 and 0.6 mg/kg gave 3/10 and 10/10 tumor-free survivors, respectively. [1]

The investigators also observed 10/10 tumor-free survivors  at a single dose of 0.5 mg/kg.  In contrast, treatment with brentuximab vedotin (Adcetris®, Seattle Genetics) only resulted in a modest delay in mean tumor growth at a single dose of 0.5 mg/kg despite this tumor expressing three times the level of the brentuximab vedotin target CD30 antigen compared to CD25.  The investigators also reported that ADCT-301 was well tolerated with no signs of toxicity at 6 mg/kg, which was, at the time of the presentation, currently the highest dose tested. [1]

Joint collaboration
ADC Therapeutics was established in 2012 by private equity firm Auven Therapeutics. In 2013, MedImmune acquired an equity stake in the company and entered into a joint collaboration for two of the antibody-drig conjugates being developed by ADC Therapeutics.

To facilitate the development, ADC Therapeutics has built a highly experienced R&D team in the UK, as well as legal, finance and EU clinical teams in Switzerland, and regulatory, clinical and manufacturing teams in the US.  The company also works closely with a number of specialist partners in Europe and the US for regulatory, clinical trial management and manufacturing activities.

In June, Chris Martin, PhD, a co-founder of Spirogen Ltd and its Chief Executive Officer leading up to the sale of Spirogen to MedImmune and a recognized leader in the ADC space, joined ADC Therapeutics as Chief Executive Officer, after having played a key role in the formation and strategy of the company as a member of its Board of Directors. Martin has also served as a member of MedImmune’s Leadership Team.

Commenting on securing the funding, Martin noted: “The significant advances we have made in progressing our pipeline of ADCs have been recognized by this financing round. In a major milestone for the company, our first ADC candidate drug entered the clinic earlier this year and we are on track to file for our second IND with the FDA by the end of October.”

“The quality of investors we have been able to attract and the size of this investment round, just over three years since the Company was founded, is a great endorsement of our strategy and potential. This financing provides the funds required to aggressively develop our pipeline of proprietary ADCs with best-in-class PBD-based warheads and linkers as an important part of the next-generation of cancer drugs, with the potential to impact cancer patients worldwide,”  Peter B. Corr, MD, PhD, Chairman of the Board of ADC Therapeutics and co-founder and Managing General Partner of Auven Therapeutics, added.

The Company was advised by Christoph Ladanyi, co-founder and Managing Director of BLMS Capital, and its corporate legal counsel Homburger AG.


Last Editorial Review: September 2, 2015

Photo/Featured Image: Queen Mary Bioenterprises Innovation Center. Photo Courtesy: Queen Mary BioEnterprises Ltd , The QMB Innovation Centre 42 New Road, London E1 2AX.

Copyright © 2015 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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ADCT-301 – A Novel Antibody-drug Conjugate Against Lymphomas – Moves Into Phase I Clinical Trial

ADC Therapeutics Sarl (Epalinges, Switzerland), a company involved in the development of antibody-drug conjugates against solid and hematological cancers, has filed an Investigational New Drug application or IND with the U.S. Food and Drug Administration (FDA) as it moves its pipeline drug ADCT-301, a novel antibody drug conjugate targeting CD25, a cell-surface antigen, which is over-expressed in many patients with lymphomas, into clinical development.

The Phase I clinical trial is expected to starts at four leading oncology centres in the United States, and then expand into two centers in the United Kingdom. Initial, up to 58 patient will be included in the adaptive designed dose-escalation study. The trial evaluates the tolerability, safety, pharmacokinetics and antitumor activity of ADCT-301 in patients with relapsed or refractory Hodgkin’s and Non-Hodgkin’s lymphoma. Subject to study results, ADC Therapeutics intends to rapidly expand the numbers of patients in the trial and the participating clinical centers.

ADCT-301 combines HuMax®-TAC™, a monoclonal antibody targeting CD25 (the alpha chain of the IL-2 receptor) created by Genmab A/S, a biotechnology company, based in Copenhagen, Denmark, with a highly potent pyrrolobenzodiazepine (PBD)-based warhead. In preclinical in vivo models, ADCT-301 exhibited strong dose-dependent anti-tumor activity against CD25-positive cell lines at low single doses. It also outperformed brentuximab vedotin (Adcetris®; Seattle Genetics), which is approved for treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma, in animal models. In preclinical studies the PBD warhead has been shown to be a highly potent killer of cancer cells even when such cancer cells are resistant to current best therapies.

Steven M. Horwitz, MD, a Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York City, is the Principal Investigator for the Phase I study. “There is significant unmet medical need for patients with relapsed or refractory disease in Hodgkin’s and non-Hodgkin’s Lymphoma. An antibody-drug conjugate targeting CD25, which is widely expressed in lymphomas, is a very rational therapeutic approach and could have very broad activity. We are delighted to be working with ADC Therapeutics to bring this potential treatment to patients,” Horwitz noted.

Significant endoresment
Michael Forer, Chief Executive Officer of ADC Therapeutics said: “The filing of our first IND is a significant milestone for ADC Therapeutics. We are delighted to be working with Memorial Sloan Kettering and other leading clinical centers. We believe this is a significant endorsement of the prospects for ADCT-301. In addition, we expect to file four more INDs with additional proprietary ADCs over the next two years as we continue to build our clinical pipeline.”

ADC Therapeutics, which was established in 2012 by private equity firm Auven Therapeutics, has a license to the PBD warheads and linker chemistry from Spirogen, a wholly-owned subsidiary of AstraZeneca’s MedImmune, and the HuMax®-TAC™ antibody was developed by Genmab under license from Medarex. In June 2013, Genmab and ADC Therapeutics entered into a Collaboration and License Agreement for the development of ADCT-301, and Genmab holds a 25% ownership share in ADCT-301.

Full pipeline
The antibody-drug conjugates being developed by ADC Therapeutics are targeted drug constructs which combine monoclonal antibodies specific to surface antigens on particular tumor cells with a cytotoxic warhead.  The company  is developing a pipeline of eleven antibody-drug conjugates and up to ten non-antibody based targeted drug constructs.


Last Editorial Review: April 16, 2015

Copyright © 2015 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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