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PEER-REVIEWED ARTICLES

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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Copyright © 2019 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 and Genmab Agree to Develop Antibody-drug Conjugate

Earlier this week Swiss-based oncology drug development company ADC Therapeutics Sarl and Danish Genmab A/S agreed to develop a new antibody-drug conjugate (ADC) combining HuMax®-TAC antibody and a PBD-based warhead and linker technology. The companies have been conducting in vitro and in vivo studies since 2012 to investigate different warhead and linker combinations with HuMax-TAC, and are now starting pre-IND preclinical development. The new product will be developed for multiple cancer indications.

HuMax-TAC is a high-affinity fully human antibody targeting CD25, a therapeutic target with strong clinical validation, which offers superior inhibition of IL-2 binding to the IL-2 receptor and also blocked the proliferation of activated T-cells that express the receptor and play an important role in inflammation. CD25 is expressed on a variety of hematological tumors and shows limited expression on normal tissues, which makes it a very attractive target for antibody-payload approaches.

Blocking T-cell mediated diseases
TAC (IL-2Rα, CD25) is the unique α-chain of the Interleukin-2 or IL-2 receptor (IL-2R). The IL-2 receptor consists of three chains. While the beta and gamma chains are shared with other cytokine receptors, the alpha chain is unique for this receptor. Once T-cells are activated they over-express the alpha chain of the IL-2R (the name TAC is derived from activated T-Cell). The IL-2R binds IL-2 (or T- cell growth factor) which is a key regulator of the normal immune system function and acts on T-lymphocytes, Blymphocytes and natural killer (NK) cells. A antibody that blocks the IL-2 receptor can inhibit T-cell proliferation. Hence, novel TAC-specific mAb targeted therapies targeting the IL-2R have the potential to block a number of T-cell mediated diseases, including organ transplant rejection and autoimmune disease, such as multiple sclerosis (MS) and uveitis.

The HuMax-TAC-ADC will be a first-in-class antibody-drug conjugate for the potential treatment of CD25-expressing lymphomas and leukemias.

“HuMax-TAC antibody has optimal characteristics for creation of an ultra-potent antibody-drug conjugate when used in combination with ADC Therapeutics’ novel PBD-based warhead and linker technology, which employs an emerging class of highly potent anticancer agents,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Pyrrolobenzodiazepine (PBD) Warheads & Linkers
ADCs developed using ADC Therapeutics’ technology combine monoclonal antibodies specific to particular tumor targets with highly potent pyrrolobenzodiazepine (PBD) based warheads developed by ADC Therapeutic’s partner Spirogen Limited. These PBD warheads are joined to antibodies by linkers that release the PBD warhead in the targeted cancer cells.

PBDs are sequence selective DNA alkylating agents with highly potent antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The unique broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds.[1]

“Our warhead payload technology enjoys exquisite potency, optimized conjugation and pharmaceutical properties that maintain activity in highly resistant cancers,” noted Peter B. Corr, Ph.D, Chairman of ADC Therapeutics. “Pre-clinical data for this product indicate the potential for curative efficacy in highly resistant populations at low ADC doses of this product in several oncology indications, an area with critical unmet needs.”

Collaboration
Genmab and ADC Therapeutics will each initially have an equal share in the product. In the first instance, ADC Therapeutics will lead and fund preclinical development. Prior to the submission of an application to conduct clinical studies in patients (IND filing), Genmab may elect to retain equal ownership of the product. Genmab will not incur any development costs prior to the IND filing decision and Genmab will maintain a minimum 25% ownership stake in the product as it moves into clinical development.


Last Editorial Review, June 24, 2013

Copyright © 2013 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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