pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity

Abstract

A growing class of immunotherapeutic agents work by redirecting components of the immune system to recognize specific markers on the surface of cancer cells and initiate a selective immune response. However, such immunotherapeutic modalities will remain confined to a relatively small subgroup of patients until two major hurdles are overcome: (1) the specific targeting of cancer cells relative to healthy cells, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidic microenvironment of solid tumors to selectively graft the surface of cancer cells with immuno-engager epitopes for directed destruction by components of the immune system. Specifically, conjugates were assembled using an antigen that recruit antibodies present in human serum, and the pH(Low) Insertion Peptide (pHLIP), a unique peptide that selectively target tumors in vivo by anchoring onto cancer cell surfaces in a pHdependent manner. We established that conjugates can recruit antibodies from human serum to the surface of cancer cells, and induce complementdependent and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells and also an engineered NK cell line. These results suggest that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent the problem of narrow windows of selectivity.

Immuno-targeting of Gram-positive Pathogens via a Cell Wall Binding Tick Antifreeze Protein

“…We opted to maintain the fluorescein hapten as it has been shown to successfully direct the recruitment of anti-FITC antibodies for killing of cancer cells. 30, 83 Additionally, to improve surface presentation of the hapten to anti-fluorescein antibodies, we positioned the fluorescein moiety to be displayed on the γ amine of an additional N -terminal lysine residue on P1 ( Figure 5B ). We directed our efforts of antibody recruitment towards E. faecalis , as P1fl demonstrated high levels of cell binding and has vital clinical applicability, being that some types of drug resistant E. faecalis can induce a vancomycin-resistant phenotype.…”

“…[14][15][16][17][18][19][20][21][22] One of the strategies being currently explored against cancer cells focuses on tagging cancer cell surfaces with small molecule haptens to promote their destruction by the immune system. [23][24][25][26][27][28][29] For example, Low and coworkers have developed anti-cancer agents, which have undergone clinical evaluation, that are composed of folate linked to the endogenous hapten, dinitrophenol (DNP), to destroy cancer cells displaying high levels of folate receptors. [30][31][32] Our group [33][34][35][36][37] and others 38,39 have developed several classes of molecules that label the surface of bacterial pathogens with small molecule haptens.…”

“…14–22 One of the strategies being currently explored against cancer cells focuses on tagging cancer cell surfaces with small molecule haptens to promote their destruction by the immune system. 23–29 For example, Low and coworkers have developed anti-cancer agents, which have undergone clinical evaluation, that are composed of folate linked to the endogenous hapten, dinitrophenol (DNP), to destroy cancer cells displaying high levels of folate receptors. 30–32…”