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First Patient Dosed in Phase Ib Clinical Trial of Camidanlumab Tesirine in Patients with Advanced Solid Tumors

A first patient has been dosed in Phase Ib clinical trial of camidanlumab tesirine, also know ADCT-301, a proprietary antibody-drug conjugate or ADC being developed by ADC Therapeutics, for the treatment of patients with advanced solid tumors.[1]

The Phase Ib clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of camidanlumab tesirine in patients with selected solid tumors that are locally advanced or metastatic.

Camidanlumab tesirine is an antibody-drug conjugate composed of HuMax®-TAC (licensed from Genmab), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin.

The HuMax-TAC monoclonal antibody targets the cell-surface antigen CD25 (the alpha chain of the Interleukin-2 receptor or IL2R-α) which is over-expressed on a variety of hematological tumors and shows limited expression on normal tissues.

IL2R-α [*], one of a heterotrimer that makes up the IL2R, has been recognized to play an important role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection. [2] Scientists have also confirmed the preponderance of CD25+ cells in hematological malignancies (malignant lymphomas including B-cell malignancies) [3] and the relationship between increased CD25 expression and poor prognosis [4] raising the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these cells in vivo.

Once bound to a CD25-expresing cell, the investigational agent is internalized into the cell where enzymes release the PBD-based payload. The intra-tumor release of its PBD payload may cause bystander killing of neighboring tumor cells. In addition, the PBD payload will trigger immunogenic cell death, which in turn will strengthen the immune response against tumor cells.

Camidanlumab tesirine is already being evaluated in relapsed and refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).[1][5]

American Society of Hematology
At the 2018 American Society of Hematology (ASH) Annual Meeting, ADC Therapeutics presented interim data on 113 patients dosed in its Phase Ia/Ib clinical trial in lymphoma. In hodgkin lymphoma patients with a median of five prior lines of therapy and no other approved therapy options, the overall response rate was 86.5%, including a 43% complete response rate, at the dose being considered for a pivotal Phase II clinical trial that the Company anticipates initiating in 2019.

“We continue to be very encouraged by the anti-tumor activity of [camidanlumab tesirine] in Hodgkin lymphoma and non-Hodgkin lymphoma,” said Jay Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics/

“In addition, based on the immune-oncology potential [camidanlumab tesirine] has demonstrated in preclinical studies, we are excited to be starting this clinical trial for ADCT-301 in solid tumors to see if we can make an impact and improve patient outcomes in multiple difficult-to-treat solid tumor cancers,” Feingold added.

Solid Tumors
At the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting, ADC Therapeutics presented preclinical data showing that an engineered version of camidanlumab tesirine demonstrated highly potent anti-tumor activity, both as a monotherapy and in combination with a checkpoint inhibitor, in multiple solid tumor models with infiltrating CD25-positive regulatory T cells (Tregs).

“[Camidanlumab tesirine] targets CD25, which is expressed on Tregs that infiltrate the local tumor environment,” noted Patrick van Berkel, PhD, Senior Vice President of Research and Development at ADC Therapeutics.

“In preclinical models, a single dose of the CD25-targeted ADC induced strong and durable anti-tumor activity against established CD25-negative solid tumors with infiltrating Tregs both as a monotherapy and in combination with a checkpoint inhibitor. Moreover, re-challenged mice did not develop new tumors indicating the CD25-targeted ADC was able to induce tumor-specific protective immunity,” Van Berkel, Ph.D, added.

The Phase Ib trial of camidanlumab tesirine in patients with advanced solid tumors has both dose escalation and cohort expansion parts. The dose escalation part is designed to establish a safe and tolerated dose and dosing schedule of camidanlumab tesirine in these patients.

The identified dose and dosing schedule will be studied in the dose expansion part. Approximately 50 patients will be enrolled in the trial.

Reference
[1] Study of ADCT-301 in Patients With Selected Advanced Solid Tumors – NCT03621982
[2] Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol Lett. 2007 Nov 30;114(1):1-8. Epub 2007 Sep 14.
[3] Srivastava MD, Srivastava A, Srivastava BI. Soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in hematologic malignancies. Leuk Lymphoma. 1994 Jan;12(3-4):241-51.
[4] Yoshida N, Oda M, Kuroda Y, Katayama Y, Okikawa Y, Masunari T, Fujiwara M, Nishisaka T, et al. Clinical significance of sIL-2R levels in B-cell lymphomas. PLoS One. 2013 Nov 13;8(11):e78730. doi: 10.1371/journal.pone.0078730. eCollection 2013.
[5] Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma – NCT02432235 


[*] The interleukin-2 (IL-2) receptor includes three different IL-2 receptor chains: α, β, and γ. Among these, the α-chain (CD25) on the cell membrane is cleaved by proteolytic processing, and the cleaved α-chain is detected as sIL-2R. The ligand of IL-2R, IL-2, plays a critical role in the development of T and NK lymphocyte as a growth factor.


Last Editorial Review: January 7, 2019

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Interim Phase I Data from Camidanlumab Tesirine (ADCT-301) Shows Encouraging Preliminary Safety and Efficacy Results

Clinical data from two ongoing Phase I clinical trials evaluating camidanlumab tesirine, also known as ADCT-301* or “Cami-T”, in important subtypes of lymphoma and leukemia show encouraging, preliminary, safety and efficacy results.

The data from these clinical trials was presented at the 59th annual meeting of the American Society of Hematology (ASH), held December 9 – 12, 2017 in Atlanta, Georgia (USA).

Mode of Action
Camidanlumab tesirine is an antibody-drug conjugate or ADC, being developed by ADC Therapeutics, comprising a human monoclonal antibody against CD25 (HuMax®-TAC, licensed from Genmab), stochastically conjugated through a dipeptide cleavable linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin with a drug-antibody ratio (DAR) of 2.3 [1][2]

Once bound to a CD25-expresing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. After internalizing, the released pyrrolobenzodiazepine (PBD) dimer payload, found among the most cytotoxic agents known, binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. [2] In turn, this eventually results in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis.


Acute myeloid leukemia is the most common leukemia in the adult population in United States. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis.

Camidanlumab tesirine … has shown an acceptable safety profile…


In vivo, single dose of camidanlumab tesirine leads to dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models.[2]

Attractive target
CD25, also known as interleukin-2 receptor alpha or IL2R-α, a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin-2 or IL-2, is an attractive target for an antibody-drug conjugate approach as it is expressed on the cell surface of a wide range of hematological malignancies, including Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma lymphoma. Interestingly, the expression of CD25 in healthy organs is restricted. [3][4]

To date, camidanlumab tesirine is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma, and in patients with relapsed or refractory CD25-positive acute myeloid leukemia and acute lymphoblastic leukemia. [5][6]

Poster 1.0: Presented at the 59th (2017) Annual Meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma. Click here to enlarge.

B-cell Hodgkin’s or non-Hodgkin’s lymphoma
The first poster presentation (1510) showed data from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies.

Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks. [7]

“Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77% overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44% complete response rate,” noted Steven M. Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator of the study.

“We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33%) and B-cell lymphomas (ORR: 19%). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II,” Horwitz added.

Key findings included:

  • For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44%) and 9 patients achieving a partial response (33%).
  • For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50%).
  • For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77%), 13 of 18 patients previously treated with a checkpoint inhibitor (72%), 9 of 14 patients who had previously undergone a stem cell transplantation (64%), and 4 of 8 patients who had previously received all three of these treatments (50%).

Adverse events.
Camidanlumab tesirine has been reasonably well tolerated.

The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30%), rash (26%), elevated gamma-glutamyltransferase (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13%), reduced platelet count (9%), elevated alanine aminotransferase (6%), anemia (6%), and rash (6%). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.

Based on the encouraging preliminary safety and efficacy results, the researchers support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.

Poster 2.0: Presented at the 59th (2017) Annual meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia. Click here to enlarge.

B-cell acute myeloid leukemia or acute lymphoblastic leukemia
Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit.

The median age of patients was 67 years and they had a median of 3 prior therapies.[8]

In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings:

  • One patient achieved a complete response with incomplete blood count recovery;
  • Camidanlumab tesirine has shown an acceptable safety profile
  • The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30%), nausea (24%), febrile neutropenia (21%), and pneumonia (21%). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21%), thrombocytopenia (15%), fatigue (12%), reduced neutrophil count (12%), and pneumonia (12%);
  • Dose escalation will continue to investigate weekly dosing.

Earlier this year interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, were 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, confirming  favorable tolerability and efficacy.

These 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). [9]


* Also see: ADC Review | Antibody-drug Conjugates – Drug map

Last editorial review: December 16, 2017

Featured Image:  ADC Therapeutics Booth | 59th Annual Meeting of the American Society of Hematology. Courtesy: © 2017. 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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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

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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

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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

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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

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