Genmab A/S, a biotechnology company, based in Copenhagen, Denmark, specializing in the creation and development of differentiated human antibody therapeutics for the treatment of cancer, confirmed that it will not exercise its co-development right for HuMax®-TAC™-ADC (ADCT-301) with Swiss-based ADC Therapeutics Sarl.

ADCT-301 is a novel antibody drug conjugate which combines the recombinant human IgG1 HuMax®-TAC™, created by Genmab under license from Medarex, with a highly potent pyrrolobenzodiazepine (PBD) warhead developed by ADC Therapeutic’s partner Spirogen Limited (a wholly-owned subsidiary of AstraZeneca’s MedImmune) and ADC Therapeutic’s own linker technology that release the PBD warhead in the targeted cancer cells.  Upon release, the PBD dimer warhead induces highly cytotoxic interstrand cross-links in the DNA minor groove.

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, which makes it a very attractive target for antibody-payload approaches.  As such, ADCT-301 has the potential to be a first-in-class antibody-drug conjugate for the treatment of CD25-expressing lymphomas and leukemias.


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. [1] Scientists have also confirmed the preponderance of CD25+ cells in hematological malignancies (malignant lymphomas including B-cell malignancies) [2] and the relationship between increased CD25 expression and poor prognosis [3] raising the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these cells in vivo.

In a number of preclinical studies ADCT-301, which has a confirmed drug-antibody ratio (DAR) of  2.3 ± 0.3, was potently cytotoxic against CD25-expressing anaplastic large cell lymphoma lines SUDHL1 (341,000 CD25 copies/cell, GI50 0.7 ng/ml) and Karpas 299 (112,000 copies/cell, GI50 3.9 ng/ml) and Hodgkin’s lymphoma line L540 (91,000 copies/cell, GI50 3.9 ng/ml). In contrast, CD25-negative Burkitt’s lymphoma line, Daudi, gave a GI50 >> 1 mg/ml.

In vivo, ADCT-301 has demonstrated dose-dependent antitumor activity against SUDHL1 and Karpas 299 xenograft and disseminated models. Furthermore ADCT-301 was well tolerated with no signs of toxicity at 6 mg/kg, currently the highest dose tested.

Development rights
While Genmab will not exercise co-development rights, the company retains 25% of the rights to the product. Under the terms of the companies’ original agreement, Genmab had a 50% ownership stake with an option to maintain equal ownership of HuMax-TAC-ADC prior to the submission of an Investigational New Drug (IND) application and fund half of the development costs. However, Genmab decided not to maintain its co-development right for HuMax-TAC-ADC, while retaining a 25% ownership stake in the product.  The original agreement between the companies dates back to June 2013. [5]

Jan van de Winkel, Ph.D., Chief Executive Officer of Danish Genmab A/S

ADC Therapeutics earlier confirmed that it had filed an Investigational New Drug application or IND with the U.S. Food and Drug Administration (FDA) for HuMax-TAC-ADC. [6]

“While we have decided not to fund co-development of HuMax-TAC-ADC with ADC Therapeutics, we are pleased to still have 25% of the rights to the product, which has potential to become a first-in-class antibody-drug conjugate therapeutic in certain hematological cancer indications,” noted Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

iDD Biotech SAS
Unrelated to the agreement with ADC Technologies, Genmab also announced that its Dutch subsidiary Genmab Holding B.V., based in Utrecht, The Netherlands, purchased antibodies and related patents and know-how from iDD Biotech SAS, a privately-held company (Société par Actions Simplifiées) based in Lyon, France, for pre-clinical stage antibodies directed to DR5, also known as Trail Receptor 2 (TRAIL-R2), an emerging cancer target.

Under the terms of the agreement, Genmab will pay iDD Biotech an upfront fee of EUR 2.5 million. Future payments range from a minimum of EUR 3.5 million to potentially EUR 101.5 million in development and sales milestones and single-digit royalties on commercialized products. This acquisition of antibody assets is synergistic with Genmab’s strategy to create a broad pipeline of differentiated therapeutic products and to leverage its deep antibody expertise to create leapfrog drugs, as it builds a sustainable business.

“We are pleased to add this exciting target and these unique DR5 antibodies to our expanding list of pre-clinical assets. This move provides Genmab with another opportunity to create potential next-generation antibody drugs which could lead to new ways of treating cancer,” Van de Winkel said.

[*] 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. [4]