Urelumab

Key takeaways

Urelumab belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Urelumab to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Urelumab from memory before moving on to harder problems.

Reference excerpt

Urelumab (BMS-663513 or anti-4-1BB antibody) is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited because it can cause severe liver toxicity.

Mechanism of action Urelumab targets the extracellular domain of CD137 (4-1BB). CD137 is a co-stimulatory molecule that’s a member of the tumor necrosis factor (TNF) receptor superfamily. The CD137 gene is located within the chromosome 1 p36 locus. CD137 is expressed on the surfaces of activated CD8+ and CD4+ T cells, natural killer (NK) cells, dendritic cells, B cells, monocytes, and neutrophils. Urelumab targets, binds to, and activates the CD137 receptor on these CD137-expressing immune cells. The activation of CD137 signaling by urelumab promotes anti-tumor immunity through a variety of mechanisms. CD137 activation by urelumab stimulates a strong cytotoxic T cell response against tumor cells which results in tumor clearance. Urelumab achieves this by promoting the proliferation and survival of activated CD8+ T cells and upregulating their activity and effector functioning by allowing for increased levels of cytokine production (IL-2 and IFN‐γ) and higher cytotoxic capacity of activated CD8+ T cells. It also results in increased formation of memory T cells, which is crucial for creating a long-term anti-tumor response. CD137 activation by urelumab also strengthens other aspects of the innate and adaptive immune response against tumor cells. CD137 activation promotes the proliferation and survival of natural killer cells which carry out antibody-dependent cell-mediated cytotoxicity of tumor cells. CD137 activation also promotes the proliferation and survival of B cells and CD4+ T cells, the differentiation of monocytes into dendritic cells, and the secretion of cytokines from these cell types.

Clinical trials Because of its ability to promote anti-tumor immunity with memory in cancer patients, Urelumab is an innovative and promising cancer immunotherapy. The first phase I trial of urelumab began in 2006 and final results were published in 2015. Current clinical trials combine Urelumab with chemotherapy (NCT00351325), chemoradiation (NCT00461110), ipilimumab (NCT00803374), rituximab (NCT01775631, NCT02420938), cetuximab (NCT02110082), and elotuzumab (NCT02252263), nivolumab (NCT02253992) for metastatic solid tumors, NSCLC, melanoma, B-cell non-Hodgkin lymphoma, colorectal cancer, and multiple myeloma. A biomarker study using CyTOF is also underway.

Liver toxicity The success of urelumab in promoting anti-tumor immunity in clinical trials has been hampered by the fact that it is dose-limited. When administered in amounts beyond the maximum tolerated dose, urelumab has resulted in hepatotoxicity in human patients enrolled in urelumab clinical studies. In phase I and II clinical trials, Urelumab caused severe hepatotoxicity in more than 5% of patients enrolled. After two hepatotoxicity-related deaths in December 2008, enrollment was halted in all urelumab clinical studies globally, but were restarted in 2012. Urelumab induces liver toxicity by activating liver Kupffer cells. The receptor FcγRIIB is expressed on both CD8+ T cells and liver Kupffer cells. Because of this, CD8+ T cell activation by Urelumab simultaneously induces the activation of liver Kupffer cells, which causes these macrophages to infiltrate the liver and cause hepatocyte damage. Results from integrated safety analyses of Urelumab dosages across Urelumab clinical studies indicates that doses of ≥1 mg/kg every three weeks will result in high levels of hepatotoxicity and transaminitis. However, Urelumab dosed at 0.1 mg/kg or lower every 3 weeks was demonstrated to be safe, and didn’t result in hepatotoxicity, and is the current recommended maximum tolerated dose in human patients enrolled in Urelumab clinical studies. While urelumab provides promising results for clinical efficacy against tumors, these responses were achieved in mouse models that administered Urelumab above this maximum tolerated dose. This issue has hindered the clinical success of urelumab today in establishing anti-tumor immunity in human cancer patients.

References

Worked examples

Example 1 — a first encounter with Urelumab

Start with the simplest possible case. Write down what Urelumab claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Urelumab before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Urelumab ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Urelumab

In research: Urelumab appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Urelumab in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Urelumab is common in secondary-school and first-year university syllabi. It links to neighbouring topics Drugs developed by Bristol Myers Squibb, Drugs not assigned an ATC code, Experimental cancer drugs, so understanding it makes those chapters shorter.
In everyday life: Look for Urelumab outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Urelumab in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Urelumab means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Urelumab out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Urelumab in simple terms?

Urelumab (BMS-663513 or anti-4-1BB antibody) is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors.

Why does Urelumab matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Urelumab?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Urelumab.