ipilimumab

Ipilimumab is a fully human IgG1 monoclonal antibody targeting CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), an inhibitory receptor expressed on activated T cells and constitutively on regulatory T cells. CTLA-4 normally competes with CD28 for binding to B7 (CD80/CD86) on antigen-presenting cells, dampening T-cell activation (the second signal in the two-signal model of T-cell activation). By blocking CTLA-4, ipilimumab prevents this inhibitory signal, allowing sustained T-cell activation and proliferation, enhancing antitumor immunity. It also may deplete intratumoral regulatory T cells via antibody-dependent cellular cytotoxicity.

Clinically, ipilimumab was the first checkpoint inhibitor approved by the FDA (2011) for metastatic melanoma, and is often combined with nivolumab (anti-PD-1) for synergistic effect in melanoma, renal cell carcinoma, and other malignancies.

Because CTLA-4 blockade removes a key brake on the immune system, ipilimumab causes immune-related adverse events (irAEs), which are the hallmark toxicity of checkpoint inhibitors. These include colitis, dermatitis (rash, pruritus), hepatitis, hypophysitis, thyroiditis, and pneumonitis. Management of severe irAEs involves corticosteroids and sometimes other immunosuppressants (e.g., infliximab for refractory colitis), with therapy interruption or discontinuation depending on severity.

High-yield board points: differentiate CTLA-4 inhibitors (ipilimumab) from PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab) — all are checkpoint inhibitors but target different points in T-cell regulation. Understand the two-signal model of T-cell activation (TCR-MHC plus CD28-B7) and how checkpoint molecules modulate this process. Know irAEs as the class-defining toxicity, distinct from typical chemotherapy toxicities (myelosuppression, mucositis).