PII-221 - TETRAVALENCY IMPACT ON BISPECIFIC ANTIBODY-ACHIEVED RECEPTOR OCCUPANCY AND TARGET DOWNREGULATION: ESTIMATION BY TRANSLATIONAL PK/RO MODEL OF CTX8371 ANTIBODY

V. Musatova¹, O. Demin², O. Demin Jr³, D. Shchelokov³; ¹INSYSBIO CY Ltd, Limassol, Cyprus, ²INSYSBIO UK Ltd, Edinburgh, UK, ³InSysBio CY.

Background: Nowadays not only bivalent bispecific antibodies (bsAb) are available, but also tri- and tetravalent ones. Antibodies with a valency of more than 2 might have different mechanisms of action compared to bivalent ones. We developed a translational PK/RO model of tetravalent bispecific antibody CTX8371б its bivalent bsAb analog and bivalent monospecific antibody to investigate the possible effects of tetravalency compared to bivalency on receptor occupancy (RO) and target internalization.

Methods: PK was described by a conventional 2-compartment model. The binding of bsAb to PD1 and PDL1 on T cells in plasma and tumor and on malignant cells in a tumor, including cis-binding with tri-, tetra-, and pentameric (tetra- and penta- only for tetravalent Ab) complexes formation was described. Parameters were identified with published data for cynomolgus monkeys, translation to the human was made using a common allometric scaling approach. RO and total target number on the cell were simulated for bivalent and tetravalent bsAbs used Q2W in different doses for further comparisons on day 100.

Results: Tetravalent bsAb CTX8371 shows a difference in simulated RO (defined as a ratio of free receptor to current total receptor) and a total PD1 and PDL1 downregulation during treatment compared to monospecific bivalent Ab, but this difference is observed only for low Ab doses [0.001 - 0.1 mg/kg]. For 0.001 mg/kg PD1 RO for CTX8371 was equal to 76%, whereas for bivalent monospecific Ab - 54%. Bivalent bsAb, targeting PD1 and PDL1 with the same binding parameters, shows almost no difference in simulated RO and total target protein downregulation compared with bivalent monospecific on the whole range of simulations [0.001 - 10 mg/kg].

Conclusion: The model shows an additional effect of tetravalency on RO and total target protein downregulation. This effect might be explained by additional tri-, tetra, and pentameric complexes formation. On low doses, the relative weight of these complexes is significant, whereas on high doses only dimeric complexes Ab-Target is observed.