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.
“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.”
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.