Exploiting innate immune effector mechanisms against the Fc domain of monoclonal antibodies (mAbs) is gaining immense popularity in anti-cancer therapy. Its mechanism of action relies on the clustering of mAbs onto a target (cancer) cell surface by binding with its Fab fragments to the target cell surface. Subsequent exposure of the Fc domain towards the external medium flags the cell for destruction by a combination of complement activation, NK-cell mediated killing and phagocytosis by macrophages. As an alternative to the use of externally administered mAbs, exploiting the presence of endogenous antibodies against haptens such as dinitrophenol, rhamnose, galactose-α-1,3-galactose, etc…, that are present in the serum of every human being could be beneficial as it circumvents the need for recombinant production and genetic engineering to make the antibody compatible with the host as well as avoiding stability issues often encountered with long term storage of mAbs. Here we report on the design, and evaluation in an onco-immunological context, of multivalent antibody recruiting constructs that can anchor to the phospholipid cell membrane trough insertion of alkyl lipids and expose multiple copies of a small molecule motif that binds endogenous antibodies. Third generation (G3) poly(propylene imine) dendrimers bearing 16 primary amines at their surface were conjugated with varying ratios of myristyl (C14) motifs and dinitrophenol (DNP) motifs using activated ester derivatives. Dendrimers composed of a 10/6 myristyl/DNP ratio afforded the most efficient antibody recruitment in vitro and could mediate phagocytosis of cancer cells. In vivo, in mouse models, we demonstrated that intratumoral injection of dendrimers afforded recruitment of (pre-administered or immunization-induced) anti-DNP antibodies, leading to a therapeutically relevant reduction in tumor growth.

Activating innate anti-tumor immune killing by antibody-recruiting hapten-lipid dendrimers

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.