Danish Biotech Develops Antibody-drug Conjugate for Treatment of Metastatic Soft Tissue Sarcoma

The Little Mermaid, Copenhagen,Denmark
The Little Mermaid, Copenhagen,Denmark

ADCendo, a biotechnology spin-out from the University of Copenhagen and the Finsen Laboratory of Rigshospitalet in Copenhagen, Denmark, developing novel antibody-drug conjugates or ADCs, confirmed that it has been accepted into the BioInnovation Institute (BII) Creation House program.

As part of the program, ADCendo has also secured a convertible loan of 10 million Danish Krone or approximately U.S. $ 1.5 million for furthering its novel antibody-drug conjugates being developed for treatment of a number of cancers.

Antibody-drug conjugates are a class of highly potent biopharmaceutical drug composed of an antibody linked, via a chemical linker, to a biologically active drug or cytotoxic compound. These agents combine the unique and very sensitive targeting capabilities of antibodies, with the potent effects of the conjugated cytotoxic drugs, allowing sensitive discrimination between healthy and cancer tissues. To date, five ADCs have received market approval and are commercially available. Nearly 100 unique antibody-drug conjugates are currently investigated in ongoing clinical trials.

Collagen receptor
The collagen receptor uPARAP/Endo180 is overexpressed by malignant cells in several non-epithelial cancers while, at the same time, in healthy adult individuals, expression is restricted to minor subsets of mesenchymal cells.

Research has shown that uPARAP/Endo180 is a rapidly recycling endocytic receptor that delivers its ‘cargo’ directly into the endosomal-lysosomal system. This opens a potential route of entry into receptor-positive cells. This makes antibody-drug conjugate mediated delivery of a targeted drug possible, functional, strategy.

Using a specific antibody against uPARAP/Endo180, raised through immunization of a uPARAP/Endo180 knock-out mouse, the ADCendo team developed a novel uPARAP-directed ADC. This investigational drug included an antibody coupled to the highly toxic dolastatin derivative, monomethyl auristatin E (MMEA), via a cathepsin-labile valine-citrulline linker.

Following publication of scientific proof-of-concept in 2017, ADCendo was established with the purpose of further developing an antibody-drug conjugates directed at a novel target receptor, uPARAP. [1][2]

This approach potentially enables targeted therapy in several cancer forms where expression of the target has been found to be highly upregulated, including soft-tissue sarcoma, osteosarcoma, glioblastoma multiforme (GBM) and triple-negative breast cancer. In addition, recent research suggests that targeting uPARAP-positive stromal cells (healthy cells surrounding a solid tumor) with this approach, may potentially offer opportunities for treating several much more commonly occurring carcinomas, including breast, colon, pancreatic, prostate, ovarian and renal cancers.

The ADCendo team: from left to right: Christoffer Nielsen, Niels Behrendt, Henrik Stage and Lars Engelholm. Not pictured is team member Andreas Hald. Courtesy: 2019 ADCendo .

Early research
“Based on our early results obtained at the Finsen laboratory, we were granted a pre-seed grant from Novo Holdings enabling us to make significant improvements to the overall performance of our early ADC candidates,” said Niels Behrendt, DSc, Ph.D, Chief Scientific Officer of ADCendo and group leader at The Finsen Laboratory.

“Our results have been very well received by our international ADC network, and with the expanded access to BII, as well as the additional financial support, we are looking forward to furthering the development of our clinical candidate. Having created the scientific basis of the company through many years of basic cancer research, we are of course very excited about this opportunity to take our results further towards clinical utilization, and we are very proud of having been selected for the Creation House program at BII,” Behrendt added.

“At the Finsen Laboratory, we have a strong focus on the translational aspects, in addition to our basic research. The successful path of ADCendo from basic cancer research by its founders at the Finsen Laboratory, to a spin-out biotech, nicely illustrates how our research strategy may contribute to development of novel, innovative anti-cancer treatments,” noted Bo T. Porse, Ph.D, head of the Finsen Laboratory.

Metastatic soft tissue sarcoma (STS)
In parallel with furthering its ADC research and development program, ADCendo is preparing pre-clinical and clinical development plans for metastatic soft tissue sarcoma (STS), a serious disease where patients have a median survival of only 12-18 months. The disease comprises of a group of heterogeneous tumors with more than 50 different histological subtypes that can be classified according to the soft tissue of origin.The most common types of sarcoma in adults include undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma), liposarcoma and leiomyosarcoma.

The American Cancer Society‘s estimates, in 2019 about 12,750 new soft tissue sarcomas will be diagnosed (7,240 in males and 5,510 in females) and about 5,270 Americans (2,840 males and 2,430 females) are expected to die of soft tissue sarcomas.

Filling the Gap
The company aims to fill the gap following the withdrawal, in early 2019, of olaratumab (Lartruvo®, Lilly Oncology), an anti-PDGFR-α antibody, which failed in the confirmatory phase III ANNOUNCE study. The study showed that olaratumab, combined with doxorubicin, did not improve survival in patients with advanced or metastatic soft tissue sarcoma (STS) compared with doxorubicin alone.[3][4]

At launch, olaratumab was the first new drug to be approved for first-line treatment of metastatic soft tissue sarcoma in 40 years, and the drug was well received and hoped to provide treatment for STS patients with substantial unmet needs.

Strategy
ADCendo aims at developing its ADC strategy for STS, based on a development track similar to olaratumab, which was granted orphan designation, fast track, breakthrough therapy designation, priority review status, and accelerated approval for STS, enabling a faster and more cost-effective clinical development path.

“ADCendo’s business strategy is aimed at moving its lead compound into the clinic for STS patients, preferably based on an orphan drug designation, and hopefully receiving conditional approval for the drug to fill the gap after Lilly’s olaratumab failure,” explained Henrik Stage, ADCendo’s Chief Executive Officer.

“Having been accepted for the BII program and receiving the convertible loan funding is an important step towards maturing the company, and preparing for the additional investments needed from investors and partners, to enable us to fulfil our ambitions of bringing our novel ADC drug to the market for treatment of patients with an unmet medical need,” Stage added.

“The goal for ADCendo is to develop a new drug for soft tissue sarcoma (STS), which is a heterogenous groups of tumors notorious for their recurrence, overall complexity, and difficulty to treat. Research from the ADCendo team has shown that the novel target, uPARAP, is highly overexpressed on the surface of cancer cells of STS tumors, making it very well suited for targeting with ADCendo’s ADCs. BII’s support on funding and business development can boost ADCendo to succeed in commercialization of the treatment to benefit patients,” said Hervør Lykke Olsen, Senior Scientific Business Developer at BioInnovation Institute.

Located in Copenhagen, Denmark, the BioInnovation Institute (BII), an initiative of the Novo Nordisk Foundation, is an international initiative for research-based innovation and entrepreneurship, embracing every phase of a life-science start-up.

ADCendo was founded in 2017 by scientists Niels Behrendt, Lars Henning Engelholm and Christoffer Nielsen from The Finsen Laboratory of Rigshospitalet and the University of Copenhagen, and Henrik Stage, a biotech-entrepreneur active in several biotech companies, and previously CEO/CFO of Santaris Pharma which was acquired by Roche in 2014. The team was in 2017 joined by Andreas Hald, an experienced scientist with a background from both basic research and the pharma industry.

Reference
[1] Nielsen CF, van Putten SM, Lund IK, Melander MC, Nørregaard KS, Jürgensen HJ, Reckzeh K, et al. The collagen receptor uPARAP/Endo180 as a novel target for antibody-drug conjugate mediated treatment of mesenchymal and leukemic cancers. Oncotarget. 2017 Jul 4;8(27):44605-44624. doi: 10.18632/oncotarget.17883. [Pubmed][Article]
[2] Engelholm LH, Melander MC, Hald A, Persson M, Madsen DH, Jürgensen HJ, Johansson K, Nielsen C, et al. Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180. J Pathol. 2016 Jan;238(1):120-33. doi: 10.1002/path.4661. Epub 2015 Nov 30.[Pubmed][Article]
[3] A Study of Doxorubicin Plus Olaratumab (LY3012207) in Participants With Advanced or Metastatic Soft Tissue Sarcoma (ANNOUNCE) – NCT02451943
[4] A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma (ANNOUNCE 2) – NCT02659020