Advancing against avelumab

Positive in vivo efficacy and pharmacokinetic data shows AVA04-VbP drug conjugate out-performed avelumab

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CAMBRIDGE, UK and SEOUL, South Korea—Avacta Group plc announced today that it has successfully demonstrated initial proof-of-concept for its proprietary new class of drug conjugate, TMAC, in a preclinical murine model of cancer. The study showed that AVA04-VbP outperformed Bavencio (avelumab), a marketed anti-PD-L1 immunotherapy.
Avacta’s tumor microenvironment activated drug conjugates (TMAC) drug conjugates combine the company’s two proprietary platforms, Affimer immunotherapies and pre|CISION chemotherapies, in a single drug molecule. The drug conjugates use a linker (incorporating the proprietary pre|CISION substrate) designed to only release the chemotherapy in the tumor microenvironment through the action of an extracellular enzyme called FAPa. This mechanism overcomes the need to target an internalizing cancer marker, as with conventional antibody drug conjugates (ADCs), and allows extremely potent chemotherapies to be combined with Affimer immune-checkpoint therapies.
AVA04-VbP combines an Affimer PD-L1 checkpoint inhibitor with an I-DASH chemotherapy warhead, addressing the acute systemic toxicity associated with I-DASH inhibitors by targeting the release of the drug warhead in the tumor microenvironment. The drug warhead induces a highly pro-inflammatory cell death, which in turn stimulates an immune response in the tumor, which is supported by the Affimer PD-L1/PD-1 signaling pathway blockade.
In a mouse syngeneic tumor model study, Avacta has shown that AVA04-VbP outperforms Bavencio, a marketed PD-L1 antibody inhibitor developed by Merck and Pfizer. Animals treated with AVA04-VbP showed a significant reduction in the rate of tumor growth with respect to those treated with Bavencio. A considerably higher level of the released I-DASH warhead was measured in the tumors, compared with very low levels in the blood. This indicates that the healthy tissues in the body are being spared exposure to the highly toxic warhead, which is central to the TMAC mechanism of action.
“These in vivo efficacy and pharmacokinetic data demonstrate initial proof-of-concept for TMAC drug conjugates and represent an important milestone for the Company,” said Dr. Alastair Smith, chief executive officer of Avacta Group. “We have received significant commercial interest in the TMAC concept, so I am delighted that we have been able to demonstrate superior efficacy and targeting of the warhead to the tumor with the first TMAC to be have tested in animals. This is hugely encouraging for the TMAC program and I look forward to keeping the market updated on future developments.”
The positive AVA04-VbP data report isn’t the only Affimer protein news out of Avacta this month. At the beginning of January, Avacta also agreed to establish a joint venture in South Korea with Daewoong Pharmaceutical Co. Ltd. The companies have entered into a collaboration and license agreement for a joint venture to develop the next generation of cell and gene therapies incorporating Affimer proteins.
“Our partnership reinforces the shared vision of both companies to design the next level of treatment paradigm, and to open up a new horizon in immunotherapeutic strategies,” noted Seng-ho Jeon, CEO of Daewoong, in a press release. “This innovative collaboration will deliver invaluable synergy and lead to new solutions with the potential to transform patients’ lives.”
The joint venture will develop a new class of mesenchymal stem cells (MSCs) that are primed to produce Affimer proteins. Affimer proteins are designed to enhance the immune-modulatory effect by reducing inflammatory or autoimmune responses.
Daewoong provides the joint venture with access to the company’s proprietary technology for generating allogeneic MSCs from a single donor to treat a large number of patients. This proprietary technology facilitates developing cell therapies as off-the-shelf products.
Avacta will develop Affimer proteins against several undisclosed targets, and transfer them to the joint venture to be incorporated into MSCs. The resulting engineered MSCs will have broad ranging therapeutic utility, depending on the Affimer proteins’ intended therapeutic purposes.
Avacta’s research and development costs will be fully covered by the joint venture, and Avacta retains the rights to commercialize the Affimer proteins outside of the field of cell therapies. Avacta has a 45% share in the joint venture, while Daewoong holds 55%. The joint venture will be operationally managed by Jeon, with a board composed of both Avacta and Daewoong representatives.
“We are very excited to establish the joint venture with Daewoong, a world-class partner, combining our powerful Affimer platform with MSCs to develop breakthrough medicines targeting immune-mediated diseases. Affimer proteins have the potential to selectively modulate signaling pathways in inflammatory diseases in order to reduce the aberrant immune response occurring in those tissues, as well as positively impacting tissue regenerative pathways meant to repair and restore normal function to the affected tissues,” Smith explained. “We look forward to working closely with the Daewoong team to advance these promising therapeutics, and get them to the patients who need them.”

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