Cancer Killers: Antibody-Drug Conjugates featuring Dr. Vangipuram Rangan

Scientific names, or the product of me mashing my keyboard randomly? Seemingly little difference.

After noting my unfunny-yet-true caption, you’re probably asking “what is this picture Adarsha has put at the beginning of this blog post/how am I supposed to understand this/am I supposed to care and why/yo is this even a legit extra credit option?”

All valid questions that I will hopefully answer soon enough! Except maybe that last one, as only time, the fates, and Professor Wang will tell.

You see, the above image is of an antibody-drug conjugate (ADC), a special molecular complex that is being touted as one of the revolutionary new ways to combat cancer by utilizing the specific nature of antibodies.

But that still doesn’t tell you how the ADC works. Or how they are made. Or…lots of other things.

Luckily, I was able to interview Dr. Vangipuram Rangan, Senior Director of Protein Chemistry at Bristol-Meyers Squibb, about ADCs in good detail. In this first video, he’ll briefly explain what antibody-drug conjugates are and what they are used for.

Alright, let’s break down that fancy-looking ADC at the beginning into a universal model of ADCs, and take a look at how they work.

This image is from www.sciencebuz.com. I swear I did not make this in MS Paint in 5 minutes (but I totally could have).

Huzzah!

The super simple explanation of that diagram is as follows: the antibody binds to a specific site on the cancer cell, and delivers a cytotoxic drug attached via linker molecule (in)to the cancer cell, killing it. That’s it! Pretty simple in theory, but actually very complicated in reality, with lots of important nuances for each of the big three components (antibody, linker, drug). Once again, Dr. Vangipuram Rangan is here to explain industry details on ADCs in a fairly simple manner.

I’m going to give some timestamps for this next, longer video, as not all of it might interest readers who are interested in a specific portion of ADCs. However, Dr. Rangan does a fantastic job covering ADCs from a broader industry perspective as well as a more specific molecular biology one. Of course, this causes the video to be longer, but no sacrifice, no victory. Or something.

TIMESTAMPS: Until 2:05, Dr. Rangan talks about the specific nature of ADCs and why that’s important in the larger context of (cancer) treatment, but if you’re just interested in the specifics of ADCs, feel free to skip that. At 3:15, Dr. Rangan explains the process by which the antibody used in the ADCs are chosen. Afterwards, the talk shifts to the mechanism (receptor-mediated endocytosis) by which the ADC is able to do its job. Finally, from 5:47 onwards, Dr. Rangan addresses the cost and difficulty issues associated with making an ADC.

It’s important to note that while the receptor-mediated endocytosis model is currently the most accepted model to explain how ADCs work, there are proposed alternatives to it. Another possible mechanism for ADC function is that the ADC binds to the target antigen on the target cell and no receptor-mediated endocytosis occurs: instead, the linker molecule is actually cleaved by enzymes released from the target cell (in response to the binding of the target antigen), releasing the cytotoxic agent in close proximity to the target cell, where it can still kill the target cell (without necessarily being internalized in conjunction with the rest of the ADC).

Speaking of the cytotoxic agent component of ADCs, how are they attached to the antibody? What governs that attachment process, and how important is the location of the drug attachment? There are many questions to be asked in this area, and the good Doctor Rangan has answers to many of them.

In this next video, Dr. Vangipuram Rangan talks about the drug-to-antibody ratio and its significance, the mechanics of conjugating the cytotoxic agents to the antibody, and some of the issues the industry must deal with when creating an ADC, such as toxicity, conjugation location, and selection of drug-to-antibody ratio (DAR).

Again, this video errs on the longer side (a lot of the conversation flows so it’s kinda hard to cut without making the video disjointed), so I’m gonna try and provide some timestamps with details.

TIMESTAMPS: Up until 1:38, Dr. Rangan gets pretty technical on the kinds of binding sites of antibodies and how the binding works, but if you’re interested in the specifics of these things, I recommend you watch it. Next comes the important topic of the drug-to-antibody ratio. Pretty self-explanatory, but Dr. Rangan explains how the industry has to interpret that value in a specific way. At 3:06, I ask (and Dr. Rangan answers) about the importance of the specificity of the site of conjugation, and which parameters companies use to determine which sites to use. Finally, at 5:33 onwards, Dr. Rangan is asked about the DAR and how pharmaceutical companies determine which DAR is ideal.

If we look back at the image at the beginning of this blog post and look at the leftmost bracket, we can see that the drug-to-antibody ratio is 3-4, meaning that per antibody, this ADC has around 3 to 4 molecules of the cytotoxic agent per antibody.

Now, onto the last but still super-important part of the ADC: the linker molecule. The linker molecule might seem to be really simple–I mean, it just connects the cytotoxic agent with the antibody, right? …Well, okay that’s mostly right, but turns out that the linker protein plays a huge role in ensuring the cytotoxic agent actually gets into the cancer cell (harder than it sounds).

In this next short video, Dr. Rangan briefly explains the  role of the linker molecule, examples of existing linker molecules, and the criterion that a linker molecule must fulfill in order to safely and properly deliver the attached cytotoxic agent to the inside of a cancer cell.

All in all, the specific nature of ADCs seem to give them a promising future in cancer treatment. Their highly specific nature also hints at potential for treatment of various other medical issues as well. In this final, brief video clip, Dr. Vangipuram Rangan explains what he thinks the future of antibody-drug conjugates is.

If you have further questions regarding ADCs, please ask them in the comments section! I mean, I’ll not be able to answer them, but odds are Dr. Vangipuram Rangan can and will. Hope you guys found this blog post to be vaguely well-written, mildly amusing at some points, and fairly informative!

~Adarsha

SUMMARYAntibody-drug conjugates (ADCs) are a relatively new biotechnology that has great potential to combat various forms of cancer by utilizing the specific natures of antibodies in conjunction with linker proteins to deliver highly cytotoxic agents to cancer cells. One can think of ADCs functioning like hyperlocalized chemotherapy. The development of ADCs is difficult due to the many parameters that must be fulfilled in order to create a viable ADC. I was able to have Dr. Vangipuram Rangan, Senior Director of Protein Chemistry at Bristol-Meyers Squibb elaborate on the nature of ADCs and relevant biotechnology in a series of short videos.

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3 comments

  1. I like it. I want it (in the hypothetical sense — glad I don’t actually need it). And Dr. Rangan is totally your uncle, don’t front.

  2. I’m completely Ok with you “borrowing” images from my website – but please give credit where credit is due, and use ‘http://sciencebuz.com” instead of just saying a ‘science website’.


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