Chicago-based AbbVie and Genmab, headquartered in Copenhagen, Denmark, have entered into a broad oncology development program in which the companies have agreed to develop and commercialize three early-stage investigational bispecific antibody therapeutics.

The companies announced that this broad collaboration agreement of early-stage investigational bispecific antibody product candidates will be supported by a major investment in a discovery and research collaboration for future differentiated antibody therapeutics focusing on oncology and hematological malignancies.

DuoBody® and HexaBody® platform technologies
Genmab’s technology consists of tree validated and proprietary next-generation antibody technologies called DuoBody® for the generation of bispecific antibodies, and HexaBody®, which creates effector function enhanced antibodies and the HexElect® platform technology, which combines two co-dependently acting HexaBody molecules to introduce selectivity while maximizing therapeutic potency and the DuoHexaBody® platform, which enhances the potential potency of bispecific antibodies through hexamerization.

Genmab’s HexaBody technology builds on natural antibody biology and enhances the assembly of antibody hexamers, or clusters of six, after target binding at the cell surface. This results in the enhancement of immune effector functions including complement-mediated killing (complement-dependent cytotoxicity). Scientists ar Genmab have shown that the HexaBody technology can transform antibodies with limited or absent complement-dependent cytotoxicity into potent, cytotoxic antibodies.

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Partnering
AbbVie and Genmab have agreed to partner in developing Genmab’s next-generation bispecific antibody programs, epcoritamab (DuoBody®-CD3xCD20), DuoHexaBody®-CD37 and DuoBody-CD3x5T4.

Epcoritamab
Epcoritamab, also known as GEN3013, is a bispecific antibody-based on Genmab’s proprietary DuoBody technology. The investigational drug is designed to target CD3, which is expressed on T cells and is part of the T cell receptor signaling complex, and CD20, a clinically well-validated therapeutic target.

The second target, CD20, is expressed on a majority of B cell malignancies, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). In a number of laboratory models, epcoritamab has shown a highly effective killing of CD20+ tumors and induced potent tumor cell lysis across a panel of B cell tumor lines. Epcoritamab is currently evaluated in a Phase I/II study for multiple hematological B cell malignancies.

Complete dose-escalation data for epcoritamab was presented at the American Society of Clinical Oncology 2020 (#ASCO20) Virtual Scientific Program. The data and preliminary activity from the Phase I/II study (NCT03625037) of subcutaneous epcoritamab in patients with relapsed / refractory B-cell non-Hodgkin lymphoma (B-NHL) are highly encouraging showing substantial single-agent activity for epcoritamab with a manageable safety profile. In the study, epcoritamab induced rapid and deep responses in heavily pretreated patients with B-NHL across different subtypes, and no dose-limiting toxicities (DLT) were observed. [1]

Discovery and Development
The collaboration combines Genmab’s discovery and development engine and next-generation bispecific antibody therapeutic candidates with AbbVie’s deep clinical expertise, innovative antibody-drug conjugate (ADC) platform and global commercial leadership in hematological cancers.

Proprietary antibodies
The discovery research collaboration will combine proprietary antibodies from both companies along with Genmab’s DuoBody technology and AbbVie’s payload and ADC technology to select and develop up to four additional differentiated next-generation antibody-based product candidates, potentially across both solid tumors and hematological malignancies.

Jan van de Winkel, Chief Executive Officer of Genmab. Photo courtesy: 2020 Genmab/Tuala Hjarnø and Torkil Stavdal
Jan van de Winkel, Chief Executive Officer of Genmab. Photo courtesy: 2020 Genmab/Tuala Hjarnø and Torkil Stavdal

Genmab’s DuoBody-CD3 technology engages and directs cytotoxic T cells selectively to tumors to elicit an immune response towards malignant tumor cells. AbbVie’s ADC technology allows the delivery of a therapeutic toxin directly to cancer cells while sparing normal, healthy cells, providing for a more targeted, less toxic treatment approach.

“This transformative collaboration will allow us to accelerate, broaden and maximize the development of some of our promising early-stage bispecific antibodies, including epcoritamab, with the ultimate goal of bringing these potential therapies much faster to cancer patients,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

“Today’s announcement marks the beginning of a new journey for Genmab that combines our world-class knowledge in antibody biology and deep expertise in truly innovative next-generation antibody technology platforms, with AbbVie’s R&D prowess and their leadership position in hematological cancers,” Van de Winkel added

“Epcoritamab is a strong fit for our robust hematological oncology franchise”, said Michael Severino, M.D., Vice Chairman and President, AbbVie.

“By combining the strengths of our two organizations, we can advance the treatment landscape for patients battling cancer,” Severino further noted.

Collaboration Details
This collaboration will provide for the joint development and commercialization of the three bispecific antibody therapeutic candidates, including:

  • epcoritamab. The companies will share commercial responsibilities in the United States and Japan, with AbbVie responsible for further global commercialization. Genmab will book net sales in the U.S. and Japan and receive tiered royalties on remaining global sales.
  • DuoHexaBody-CD37, DuoBody-CD3x5T4, and any product candidates developed as a result of the companies’ discovery research collaboration, Genmab and AbbVie will share responsibilities for global development and commercialization in the U.S. and Japan.

As part of the agreement, Genmab retains the right to co-commercialize these products, along with AbbVie, outside of the U.S. and Japan. For the discovery research partnership, Genmab will conduct Phase I studies for these programs. AbbVie retains the right to opt-in to program development.

Financials
Under the terms of the agreement, AbbVie will pay Genmab U.S. $ 750 million in upfront payment with the potential for Genmab to receive up to USD 3.15 billion in additional development, regulatory and sales milestone payments for all programs as well as tiered royalties between 22% and 26% on net sales for epcoritamab outside the U.S. and Japan.

Except for these royalty-bearing sales, the two companies will share in pre-tax profits from the sale of products on a 50:50 basis. Included in these potential milestones are up to US $ 1.15 billion in payments related to clinical development and commercial success across the three existing bispecific antibody programs. In addition, if all four next-generation antibody product candidates developed as a result of the discovery research collaboration are successful, Genmab is eligible to receive up to USD 2.0 billion in option exercise and success-based milestone payments.

Clinical trial
GEN3013 (DuoBody®-CD3xCD20) Safety Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma – NCT03625037

Reference
[1] Hutchings M, Lugtenburg P, Mous R, Clausen MR, Chamuleau M, Linton K, Rule S, Lopez JS, er al. Epcoritamab (GEN3013; DuoBody-CD3×CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL): Complete dose escalation data and efficacy results from a phase I/II trial. J Clin Oncol 38: 2020 (suppl; abstr 8009) 10.1200/JCO.2020.38.15_suppl.8009 [Abstract]