Are Monoclonal Antibodies Considered Immunotherapy?
Yes, monoclonal antibodies (mAbs) are definitively considered a form of immunotherapy, as they work by modulating the immune system to target disease, whether by blocking immune checkpoints to enhance anti-tumor immunity or by directly targeting specific antigens to activate immune effector functions. 1, 2
Definition and Classification
Monoclonal antibodies represent a major class of immunotherapy that has transformed cancer treatment over the past decade. 1
Immune checkpoint inhibitors (ICIs) such as nivolumab (anti-PD-1), pembrolizumab (anti-PD-1), ipilimumab (anti-CTLA-4), and atezolizumab, durvalumab, and avelumab (anti-PD-L1) are explicitly classified as immunotherapy agents that work by blocking inhibitory pathways and restoring T cell-mediated cytotoxicity. 1
The FDA drug label for nivolumab describes it as "a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response." 2
These agents are distinguished from traditional chemotherapy by their mechanism: they enhance natural immune system functions rather than directly killing cancer cells through cytotoxic mechanisms. 3, 4
Mechanisms That Define Them as Immunotherapy
The classification of mAbs as immunotherapy is based on their fundamental mechanisms of action:
Immune checkpoint blockade: Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies prevent the binding of inhibitory ligands to their receptors on T cells, restoring T cell-mediated cytotoxicity and allowing the immune system to fight cancer. 2
Activation of innate immune effector functions: Many therapeutic mAbs (including anti-HER2 and anti-CD20 agents) function primarily through engagement with Fc receptors to activate antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and other innate immune mechanisms. 5
Induction of long-lasting anti-tumor immune responses: Unlike chemotherapy, mAbs can promote durable immune memory, leading to sustained responses even after treatment discontinuation. 3
Clinical Context and Guidelines
Multiple authoritative guidelines explicitly refer to monoclonal antibodies as immunotherapy:
The Society for Immunotherapy of Cancer (SITC) 2017 consensus recommendations specifically address "managing toxicities associated with immune checkpoint inhibitor therapy," referring to these mAb agents as immunotherapy throughout. 1
The 2016 Annals of Oncology guidelines discuss "immune checkpoint blockade (ICB) immunotherapy" and state that "monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1" are "now considered to be a main component of cancer therapy." 1
The 2019 Journal for ImmunoTherapy of Cancer guidelines discuss immune checkpoint inhibitors as immunotherapy agents, noting that "the monoclonal antibodies prevent the binding of PD-1 to its ligand PD-L1, restore the T cell-mediated cytotoxicity." 1
Important Distinctions
Not all monoclonal antibodies function identically as immunotherapy:
Immune checkpoint inhibitors work by removing brakes on the immune system and are the prototypical immunotherapy mAbs. 1
Tumor-targeting mAbs (e.g., anti-HER2, anti-CD20) primarily activate innate immune effector mechanisms but are still considered immunotherapy because they harness immune cells to eliminate cancer. 5
Bispecific antibodies used in multiple myeloma are explicitly discussed as immunotherapy with similar toxicity profiles to CAR T-cell therapy due to their immune mechanisms of action. 1
Clinical Implications
The classification of mAbs as immunotherapy has critical clinical implications:
Unique toxicity profile: These agents cause immune-related adverse events (irAEs) rather than traditional chemotherapy toxicities, requiring different management strategies including immunosuppression with corticosteroids. 1, 2
Infection risk: Because they modulate immune function, these agents can increase susceptibility to opportunistic infections including tuberculosis reactivation, requiring specific screening and prophylaxis protocols. 1
Delayed and prolonged effects: Immunotherapy-related adverse events typically have delayed onset and prolonged duration compared to chemotherapy, and can even occur after treatment discontinuation. 1, 2