Avacta will be in the clinic with its lead pre|CISIONTM targeted chemotherapy programme in mid-2020 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|CISIONTM 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 and TMAC drug conjugates. The lead pre|CISIONTM programme 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|CISIONTM pro-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 prodrug form, the doxorubicin drug moiety is neither cell permeable nor able to intercalate DNA (the cell killing mode of action of doxorubicin) – meaning that the prodrug circulates in the body as an inert agent. In the solid tumour microenvironment, where the level of the enzyme FAPα (fibroblast activating protein alpha) is substantially higher than in the heart or elsewhere in the body, the FAP 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 is planning to test AVA6000 in a phase I trial in soft tissue sarcoma patients in mid-2020. A prodrug 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.
The PD-L1/PD-1 axis is a negative regulator of immune activation – that is, it turns off the immune response in tumours – and this “checkpoint” pathway is considered a foundational target for drug development within the immuno-oncology field. AVA004 is a novel Affimer-based agent that selectively binds to and inhibits the interaction of PD-L1 on tumour cells with PD-1 on immune cells and so prevents this signalling pathway inactivating T-cells in the tumour microenvironment. Pre-clinical pharmacodynamics and toxicology studies of AVA004 demonstrated marked pharmacological activity and the agent is well tolerated at effective doses with a wide margin of safety. In animal models, the AVA-004 PD-L1 inhibitor displayed pharmacokinetics properties distinct from currently approved PD-L1 antibodies.
Avacta’s AVA-004 drug candidate is intended to provide first-time-in-human safety and tolerability data for the Affimer® platform, and underpin the development of PD-L1 anchored bispecifics, for use in combination with Avacta’s proprietary pre|CISIONTM prodrugs as combination therapies and in TMAC® drug conjugates.
The ability to encode AVA004 into DNA or mRNA permits the delivery of the coding sequence into the tumour such as through an oncolytic virus or nucleic acid transfection. We are working with several collaborators to explore the use of encoded Affimer® therapeutics for localised expression in the tumour with reduced systemic exposure and to impart combinatorial treatment approaches with a single injection.
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.
AVA027 a bifunctional fusion protein composed of a AVA004 PD-L1 inhibitory Affimer® molecules fused to the extracellular domain of human transforming growth factor–β (TGF-β) receptor II, which functions as a “trap” for all three TGF-β isoforms. This dual functioning biotherapeutic is designed to simultaneously block the two immunosuppressive pathways to overcome otherwise poorly addressable tumor biology.
TGF-b is widely known to have pleiotropic effects directly on cancer cells, including roles in epithelial-mesenchymal transition, invasion and metastasis. In addition to effects on cancer cells, the roles of TGF-β in remodeling the tumour microenvironment so as to suppress T cell infiltration into the tumour, as well as inducing fibrosis and angiogenesis in the tumour, have also been extensively characterised. AVA027 is designed to leverage the insights around the central role of TGF-β in tumours to inhibit cancer progression while simultaneously blockading the PD-L1/PD-1 checkpoint pathway to make sure that T-cells in the tumour microenvironment remain active against the tumour.
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 rug 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® (AVA004/100) 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.