Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells

Figures & data

Table 1. Mechanisms of action of antitumor mAbs

Class	Comments	Examples
Direct induction of cell death	Activation of a death program as direct consequence of antibody binding.
Subclass
mAbs inducing non-apoptotic cell death	Induction of death mediated by lysosome membrane permeabilization and production of reactive oxygen species.	Tositumomab^10 Obinutuzumab^11
Anti-TRAIL/DR mAbs	Induction of apoptotic cell death with FcγR-positive immune cells promoting mAb-mediated clustering of the TRAIL-R to drive apoptotic signaling.	Mapatumumab^15 Lexatumumab^16^,^17 Drozitumab^18 Conatumumab^19 TAS266^20
Class
Inhibition of tumor-promoting growth or survival signals.	Quiescence, autophagy or indirect cell death due to deprivation of growth or survival signals as possible consequences.
Subclass
Neutralization of tumor-promoting ligands.	Several mAbs against angiogenic growth factors in development, few against tumor cell growth factors.	Bevacizumab^20
Binding to cell surface receptors or co-receptors.	Lack of activity of anti-EGFR mAbs in the presence of activating KRAS mutations is current best evidence for this mechanism of action.	Trastuzumab^30 Cetuximab^31 Panitumumab^32
Class
Recruitment of FcγR-positive immune cells.	Immune cells expressing activatory FcγRs can mediate ADCC or phagocytosis.	Rituximab^9 Trastuzumab^34
Complement activation.	Complement activation may have negative effects: infusion toxicity, inhibition of ADCC, tumor growth-promoting effects.	Ofatumumab^36
Promotion of an adaptive antitumor immune response.
Subclass
Inhibition of immune suppressive pathways.	Limited number of patients (typically 10–15%) respond. Many responders have immune-related (“autoimmune-like”) adverse events.	Ipilimumab^42^,^43
Direct promotion of active antitumor immunization.	Induction of active antitumor immunity plays a still ill-defined role in the overall antitumor efficacy of these mAbs.	Rituximab^46^-^49 Trastuzumab^50^-^53

Figure 1. Improving accumulation and interactions between mAbs and immune cells in tumors. (A) In tumor tissues levels of mAbs or immune cells may be too low to interact and kill tumor cells by ADCC or phagocytosis. (B) In the presence of promoter drug(s) tumor accumulation of mAbs or immune cells may achieve levels sufficient to interact and kill some tumor cells (tumor cell with dotted contour). (C) In the presence of mAbs binding with higher affinity to FcγR-positive immune cells, interactions may take place and kill some tumor cells. (D) In the presence of promoter drug(s) and mAbs binding with higher affinity to FcγR-positive immune cells, a higher number of interactions may take place than with either approach alone, and a large number of tumor cells may be killed.

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