Avacta took its lead pre|CISION™ targeted chemotherapy programme into the clinic in summer 2021 and has a pre-clinical pipeline of Affimer® immunotherapy candidates.
Avacta’s long term focus is on achieving a more durable response for patients through synergy of the innate immune response to pre|CISION™ FAPα activated chemotherapies with the adaptive immune response to Affimer® immunotherapies in the form of co-administered combinations and in novel tumour-microenvironment activated drug conjugates (TMAC®).
Its lead Affimer® programme is a PD-L1 antagonist which will form the basis of future bispecifics, immunocytokines and TMAC drug conjugates. The lead pre|CISION™ programme, AVA6000, is a tumour targeted form of doxorubicin.
Beyond these two main programmes, the company is exploring a number of I-O antagonists and agonists, and other pre|CISION™ FAPα activated drugs, to support future programmes and partnering.
Click on the red bars in the pipeline infographic below for more information.
AVA6000 is the first-in-class FAPα activated prodrug based on the pre|CISION platform, providing a prodrug form of doxorubicin with an improved safety profile enabling broader use in oncology, particularly in combinations with immuno-oncology drug agents.
In its FAPα activated form, the doxorubicin drug moiety is not cell permeable – therefore not able to intercalate DNA and cause DNA strand breaks (the cell killing mode of action of doxorubicin) – meaning that AVA6000 circulates in the body as an inert agent. In the tumour microenvironment, where the level of the enzyme FAPα (fibroblast activating protein alpha) is substantially higher than elsewhere in the body, the FAPα substrate is cleaved and the active doxorubicin drug is released causing a significant differential targeting of tumour tissue compared with healthy tissue.
Our preclinical animal studies indicated that administration of conventional doxorubicin resulted in approximately the same concentration of the drug in both heart tissue as in tumour tissue. In contrast AVA6000, even when administered at doses much higher than could be tolerated for doxorubicin itself, produced less doxorubicin exposure in the heart while producing 18 times as much doxorubicin in the target tumour tissue compared with the heart. Avacta dosed the first patient in an ongoing Phase I trial in summer 2021. A FAPα activated doxorubicin with a significantly improved safety profile should result in an expanded eligible patient population in the indications to which doxorubicin is currently limited because of cardiotoxicity issues, longer dosing regimens and should provide for a much more widespread utility across the field of oncology.
AVA021 is an Affimer® bispecific including Affimer® inhibitors of both the PD-L1 and LAG-3 mediated checkpoint pathways. The molecule is designed to prevent PD-L1-mediated inactivation of an antitumor immune response, revive exhausted T cells through reversal of LAG-3 signalling and by virtue of the targets of the bispecific being on two separate cells in the tumour microenvironment, activate T cells to engage and kill PD-L1 positive tumour cells and tumour-supporting stromal cells.
Despite advances with therapies targeting the PD-1/PD-L1 pathway, many patients are refractory to or relapse following treatment. Resistance to anti-PD-(L)1 treatment in these patients is often associated with upregulation of other checkpoint pathways, particularly checkpoint pathways which cause T cell exhaustion and inactivation in the tumour such as the LAG-3 checkpoint. It has been observed that antibodies that bind to LAG-3 and inhibit its interaction with MHC II are capable of reinvigorating exhausted T cells. Avacta’s LAG-3 inhibitory Affimer® binds to LAG-3 and inhibits the binding of MHC II, reversing the mechanism by which it produces the T cell exhaustion and reactivating these tumour-fighting T cells.
AVA021 is a bispecific Affimer® designed to produce dual checkpoint blockade of these two pathways.
TMAC® utilises the proprietary pre|CISION™ substrate to provide for the selective release of a drug moiety by FAPα. These FAP-activated Affimer® drug conjugates are designed to release drug moieties in the extracellular space of the tumour, rather than inside the tumour cell as is the case with traditional antibody-drug conjugates (ADCs). This novel class of drug conjugates is terms “tumour microenvironment activated drug conjugates” or TMACs. In the TMAC® format, Avacta can deliver otherwise acutely toxic immune activating molecules, which circulate in an inert form as the conjugate but which release potent activators of innate immunity when the linker is cleaved by FAPα in the tumour and the Affimer® also provides adaptive immune therapeutic activity.
In the lead Affimer® TMAC® (AVA04-VbP) an anti-PD-L1 Affimer conjugated to an I-DASH inhibitor through the linker comprising the pre|CISIONTM FAP-sensitive substrate. In animal models, this combination produces full regression and T-cell mediated immunity to rechallenge. I-DASH inhibitors are selectively toxic to macrophage and induce pyroptosis and produce inflammatory signals for both innate and adaptive immunity and promotes tumor infiltration. In the TMAC, the I-DASH inhibitor is released extracellularly and the PD-L1 is not internalized rapidly and therefore inhibits the PD-L1/PD-1 signalling pathway in the tumour microenvironment .
The I-DASH-PD-L1 Affimer® TMAC® addresses the acute toxicity associated with I-DASH inhibitors and can be similarly used with STING agonists and TLR7/8 agonists.
Avacta and Daewoong Pharmaceutical Co. Ltd. have established a joint venture in South Korea, and entered into a collaboration and license agreement for the joint venture to develop the next generation of cell and gene therapies incorporating Affimer proteins to enhance the immune-modulatory effects.
Mesenchymal stem cells (MSCs) are promising agents for the treatment of autoimmune and inflammatory diseases. The joint venture will develop a new class of MSCs that are primed to produce Affimer proteins, which are designed to enhance the immune-modulatory effect when administered to patients, by reducing inflammatory or autoimmune responses.
Daewoong will provide the joint venture with access to its 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 which will be transferred 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.