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 FAP?. 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 FAP? 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|CISION^TM 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.