Aptevo - Model APVO436 (anti-CD123 x anti-CD3) - Optimized ADAPTIR Bispecific Antibody

In preclinical studies, APVO436 was shown to redirect T-cell cytotoxicity against CD123-expressing tumor cells in both in vitro and in vivo assays. These data show that APVO436:

• Has an antibody-like serum half-life in mice of up to 12.5 days – significantly longer than first generation ADAPTIR candidates and other bispecific candidates in development
• Induced potent, dose-dependent T-cell mediated lysis (killing) of CD123-expressing AML cell lines, accompanied by target-specific T-cell activation and proliferation
• Possesses low (nM) binding affinity; bound with high affinity to human and cynomolgus CD123-expressing cells with EC50 values in the low nanomolar range
• Dose-dependently inhibited tumor growth and significantly prolonged survival compared to vehicle-treated animals in a Xenograft tumor model of AML

Preclinical data presented at the 2018 and 2019 American Association for Cancer Research Annual Meeting compared APVO436 with an Aptevo-generated version of Macrogenics’ CD123 x CD3 dual-affinity re-targeting (D.A.R.T.) molecule, MGD006. This preclinical study evaluated T-cell activation, proliferation, cytotoxicity and cytokine secretion.

The data showed that APVO436 and the Aptevo-generated version of MDG006 were both effective at stimulating a tumor-directed immune response by inducing comparable T-cell activation, proliferation and cytotoxicity. However, in these preclinical studies, APVO436 induced lower levels of several T-cell cytokines, suggesting a potential safety advantage with APVO436.

Cytokine release syndrome (CRS) is a significant concern with T-cell activating therapies and has been associated with severe complications in clinical trials. The preclinical data demonstrating potent T-cell cytotoxicity of tumors expressing CD123 with limited cytokine release, suggest that APVO436 has the potential for increased clinical benefit and a favorable safety profile.

Additional data presented at the 2018 and 2019 AACR annual meetings show that APVO436:

• Induces the generation of functional memory T cells with cytolytic function from naive T cells
• Has good tolerability, antibody-like clearance and volume of distribution parameters
• Has an extended serum half-life of 4.5 days in a relevant non-clinical species
• Binds human CD123 and CD3-expressing cells with EC50 values in the low nM range and demonstrates potent target specific activity against CD123 expressing tumor cell lines at low effector to target ratios
• Potently induces endogenous T-cell activation and proliferation accompanied by depletion of CD123 expressing cells in experiments with primary AML subject samples and normal donor samples
• Demonstrates potent cytotoxic activity from antigen-expanded T cells from both normal and AML subject samples in the presence of CD123+ tumor cells upon re-exposure to APVO436
• Results in rapid and significant reduction in skeletal tumor burden indicating migration and engagement of T cells at the tumor site, in mice with established disseminated Molm-13 tumors and IV-implanted human T cells in therapeutic preclinical animal studies
• Induces lower levels of multiple cytokines compared to a different CD123 x CD3 format, when T cells were stimulated in the presence of CD123+ tumor cells