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I read that ADCs (Antibody-Drug Conjugates) act by a -mab for a particular target being bonded to a cytotoxic compound. From my high-school-with-crayons knowledge of antibodies, however, one part of the mechanism stands out as being strange: the internalisaiton of the complex into the cell.

In my head, antibodies are either free in plasma or expressed bound to the surface of cells. How and why (mechanistically/evolutionarily/functionally) does this antibody internalisation take place? Is it a natural process in most organisms, or a backdoor which must be engineered into the ADC?

The usual sources for neophytes are quiet in this area, and the advanced material is bewildering.

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closed as too broad by MattDMo, rg255, CKM, AliceD, AMR Feb 3 '16 at 19:34

Please edit the question to limit it to a specific problem with enough detail to identify an adequate answer. Avoid asking multiple distinct questions at once. See the How to Ask page for help clarifying this question. If this question can be reworded to fit the rules in the help center, please edit the question.

  • $\begingroup$ It's a natural process, endocytosis, but endocytosis is also very complex. If you can gain access, really good article, but some general conclusions: "There are many distinct endocytic pathways that coexist in mammalian cells. Although some cargoes enter exclusively by one pathway, most cargoes can enter by several pathways. Any endocytic mechanism requires the coordinated action of proteins and lipids. The best-understood mechanism is clathrin-mediated endocytosis" $\endgroup$ – CKM Feb 2 '16 at 0:29
  • $\begingroup$ This is actually an extremely broad question, which is why I have voted to close. As @Kendall indicates, the primary (but not only) method of antibody internalization is endocytosis, but there are multiple different forms, and the exact mechanism will depend on the structure of the Ab, its target, where it binds, and the physiological context (normal vs. cancerous cells, etc.). The Annual Reviews article linked might be a little above your head (if you can get access to it), so I'd start with the wiki article I linked, as well as google searches. $\endgroup$ – MattDMo Feb 2 '16 at 16:45
  • $\begingroup$ Actually, knowledge that the process is called endocytosis helped me greatly in searching, and I've learnt a lot about the process today. I'll take a look at the review article tomorrow. I think it likely that this question with an answer along the lines of the comments above would help a fair few people, but vote as you will to make the place as it should be. $\endgroup$ – Dan Sheppard Feb 2 '16 at 23:01
  • $\begingroup$ @Kendall perhaps you can add a bit on Fc receptors and convert your comment to an answer. $\endgroup$ – WYSIWYG Feb 3 '16 at 5:23
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What we're basically looking at with ADC internalization

enter image description here Courtesy of Bayer

So the way an ADC works: The antibody-drug conugate binds to a target antigen like a transmembrane receptor, the cell in response engulfs the entire complex and send it to an endosome. What the cell can do with the endosome depends on the cargo. Digressing, the ADC internalization mechanism is often attributed to receptor-mediated endocytosis, where the most prominent mechanism of receptor internalization is the clathrin-mediated pathway. We're going to be referring here most of the time.

Clathrin-mediated endocytosis commences with the recruitment of adaptor proteins, accessory proteins and a clathrin polymeric lattice to phosphatidylinositol-4,5-bisphosphate-enriched plasma membrane regions

A common adaptor protein here is AP2 that's capable of binding to motifs present on the cytoplasmic tails of membrane receptors. What it's doing is selecting which receptors are the cargo. Then the clathrin mobilizes to the now-enriched membrane regions, and the polymerization of clathrin causes the membrane to displace and curve. Dynamins, large helical GTPase proteins capable of stretching the invagination in the membrane to a vesicle, bind the phosphatidylinositol-4,5-bisphosphates in the membrane, and may work in concert with BAR domain-containing proteins and actin tension to stretch the membrane into a vesicle and cut it away (Doherty & McMahon, 2009).

Obviously there's some missing information, as we don't fully understand it. I think reading the first reference, published in mAbs in 2013, is a really good place to start however!

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