Binding Strength,\nNot Valency, Dictates Accumulation\nand Penetration of Affinity Targeted Macromolecules into Solid Tumors

The efficacy of tumor-targeted therapeutics, engineered\nto engage\nspecific cellular receptors to promote accumulation and penetration,\nis strongly influenced by the carrier’s affinity for its target\nand the valency of binding molecules incorporated into the carrier.\nPrevious research has primarily focused on improving targeting by\naugmenting the number of binding proteins on the carrier, inadvertently\nraising avidity without isolating the individual effects of binding\nstrength and valency. Herein, we precisely evaluate the impact of\nmultivalency on tumor targeting with a recombinant approach to independently\ncontrol valency, avidity, and size. Our findings reveal that constructs\nwith equivalent binding strength exhibit comparable receptor engagement\nand tumor extravasation, regardless of valency. Moreover, excessive\navidity adversely affected tumor accumulation and penetration, with\nthe highest-avidity construct showing diminished exposure. These results\nindicate that overall binding strength, not valency, is the primary\ndeterminant of tumor targeting, providing valuable insights for designing\neffective macromolecular drug carriers.