Friday, August 30, 2019 - Aug 30th, 2019 - 5 Things in ADCs this Week

Hello all,

It’s been almost three weeks since my last update which means that there is a massive amount of material to cover and I can’t get to it all in this little update. 

If you want to check out all of the links that I have aggregated over the past three weeks, go over to and click on the ADC Links Section Header.  In these posts I just aggregate all of the relevant links that I find before winnowing down for these update articles.  But it you want to quickly see anything and everything that I thought was related to ADCs, then this is the place.

While you’re there, click on the list to join the mailing list, and then you can get every post directly to your inbox.  We had quite a few people join after the last posting, so come join the cool kids and gets your ADCDaily posts automatically.

And one last thing.  I am excited to announce that I will be hosting a Webinar next month.  It will be chock full of ADCs and DoEs.  I will do my best not to get too excited, but I most certainly love geeking out with DoEs and we have some pretty cool case studies planned for you.  It’s being held on Sep 24th at 11 EST.  Hope to see you all there.

And with that, it’s time for our five things this week…

Tuesday, August 27, 2019

ADC Links - Aug 27rd, 2019

Webinars -

Regulatory -

US senators accuse Novartis execs of greed for hiding manipulated Zolgensma data — and the next step could affect the industry
Endpoints News
- This story is huge and won't be going away any time soon.  This line seems pertinent to us, "this attack includes a shot right over the industry’s bow — with potential consequences for all drug developers"

The FDA’s very public slap of Novartis’ red face is a warning to the entire industry — don’t downplay it
Endpoints News
-Wow, this grenade just keeps getting bigger and bigger.  I think we can all expect blowback from this one

Statement on data accuracy issues with recently approved gene therapy
- It's never a good thing when you have to have a direct statement about your work from Dr. Peter Marks, the Director of CBER at the FDA.  But here is a perfect reason why it is better to read articles from the original source instead of the news aggregators viewpoint.  This line sticks out, "The FDA is carefully assessing this situation and remains confident that Zolgensma should remain on the market."  It sounds to me like there are taking the issue seriously, but that when the dust settles, things are going to be OK for Zolgensma even though there are clearly going to be some casualties along the way

Faced with another ethics scandal, Novartis CEO Vas Narasimhan assures analysts they tried to do 'the right thing'
Endpoints News
- I mean, after all of these reports, I still have to think about what amount of power one scientist can have.  Because really, this doesn't sound like systemic fraud, it sounds like a person or small group of people did a slight augmentation of their results to make their bosses happy.  Obviously this is wrong, but I think it is also something that every single person in lab can relate to

FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor
- Here is an interesting trend.  The FDA is getting more open to approvals which are focused on a specific biomarker instead of the tumor type or location.  These are not in the ADC space yet, however this is specifically what ADCs do.  They bind a specific biomarker and then get to work.  Currently, we are seeing ADCs get approved for one type, and then attempt to expand the types over time.  This trend might render that unnecessary and allow for HER2 ADCs to target any tumor with HER2 overexpression

Industry -

A top analyst spotlights a wave of biotech startups looking to catapult onto Nasdaq — or get bought out
Endpoints News
- As I always say, the best leading indicator for our market is $$$.  So signs like this are a good thing.  Investment is up, and so is M&A.  All of these things make it more profitable to be a biotech startup, and since that is where a big portion of ADC companies live, this is a good thing

The UK company Antikor Biopharma has received a €2.8M ($3.1M) investment from the Hong Kong company Essex Bio-Investment
- Antikor has a little bit thicker wallets today after a $3.1M investment from Essex Bio-Investment.  Now they will have a chance to further their FDC (Fragment Drug-Conjugates) technology

How Biotech Startup Funding Will Change in the Next 10 Years
YCombinator Blog
- Alright, so lets take this one with a big grain of salt.  As I often say, never ask a barber if you need a haircut.  However, this is an interesting take on the potential future of biotech.  Although there is the inherit difference in that YC makes apps and algorithms while we make complex chemicals for use in even more complex systems and that will always be true.  You don't see YC startups trying to upend Exxon or Anheiser-Busch because it took them 100 years to build the distribution network that they currently have, and the VC model doesn't have that kind of patience

ADC Therapeutics and SOPHiA GENETICS Partner for Biomarker Discovery in Pivotal Phase II Clinical Trial
Global Newswire
- And in a nice corollary to the article directly above this one.  SOPHiA GENETICS is trying to bring some deep learning into ADC clinical trials.  This looks like a fishing expedition for now, but if this bears fruit and they can use this to improve patients outcomes, then this could be a really interesting collaboration

Road Tripping Treatments
AbbVie Blog
- Here is another example of non-oncology ADCs.  The team at AbbVie spent five years researching an application of ADCs in immune-mediated diseases.  After 100 different linkers and 200 different payloads they finally have a candidate.  This is a cool story, and some really incredible work

Araris Biotech AG closes seed financing round of CHF 2.5 million
Global Newswire
- It's time to welcome a newcomer to the ADC world.  Araris has closed their seed round and they are looking to develop their own ADCs using a proprietary conjugation technology which can be applied to native antibodies.  Hopefully this is just the first of many positive news stories

GSK's Hal Barron heralds their second positive PhIII for crucial anti-BCMA therapy, pointing to a push for quick OKs in a crowded field
Endpoints News
- The pressure is on for GSK to have some success with their belantamab mafodotin ADC currently in Phase III trials.  So far, all signs are positive, but win or lose, this is a major event for GSK.  There is a lot of competition for BCMA targets, but as the CEO of SeaGen states, "Its in a vial."  Which at the end of the day is worth way more than any mouse models could be

Manuscripts -
Prodrugs as drug delivery system in oncology
Cancer Chemotherapy and Pharmacology
- Here is a fantastic review of Prodrugs in oncology.  The timing is perfect as in the last article I suggested the possibility of doing something like this but this article is better and more complete than anything I would be able to do.

Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody–Drug Conjugates (ADCs)
ACS Med Chem Letters
- One of the prominent themes of World ADC London this year was the modification of DNA intercolating payloads in order to increase the therapeutic window of ADC therapies.  Here the team at ImmunoGen is showing an example of what this can look like and how to synthesize new and improved payloads for use in ADC trials

Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis
- Here is a pretty cool example of a novel payload mechanism on an ADC.  Here the authors were looking at a transcription factor inhibitor (TFIIH) bound to an antibody.  They showed some success in their model but while this is still a long way off, it is interesting to see research moving away from HPAPI as this might be a way to open up that therapeutic window

Simultaneous quantification of total antibody and antibody-conjugated drug for XMT-1522 in human plasma using immunocapture-liquid chromatography/mass spectrometry.
J Pharm Biomed Anal
- This is a pretty cool manuscript describing how they analyze plasma samples for ADC and antibody during their Phase I clinical trial.  If that weren't cool enough, it also shows an example of a mass spec method being validated for clinical results which is both rare and impressive.  Recently the FDA put out a guidance document alluding to their expectation that this would be happening more and more

A Superglue for ADCs: Connecting the Cytsteine Residues of a Tumor-sensing Antibody to a Payload
- German scientists have developed a new and novel linker technology to be applied to ADCs.  They are hoping to go the opposite route of cleavable linkers and build something robust enough to eliminate the problem of free drug cleavage in the bloodstream

A Case Study Comparing Heterogeneous Lysine- and Site-Specific Cysteine-Conjugated Maytansinoid Antibody-Drug Conjugates (ADCs) Illustrates the Benefits of Lysine Conjugation
Mol Pharmaceutics
- The trend in ADCs for the past couple of years is to move away from stochastic conjugation and towards site-specific.  The argument goes that greater homogeneity will result in greater effectivity.  However, this paper serves as a case in point to the contrary.  And as might be expected.  The final result is: its complicated.  Take a look if you are willing to buck dogma and go against the ADC orthodoxy for a bit

Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody–Drug Conjugates (ADCs)
Medicinal Chemistry Letters
- Nice article on the effect of stereochemistry in PBD linker development.  They were looking at different combinations of l- and d-alanyl groups in the labile region of the linker and seeing their effect on therapeutic index.  Its nice to see some work on the foundational science behind ADC construction in a world so heavily biased by what is on trend these days (ie. PBDs are bad, and site-specific conjugation is good)

Alteration of Physicochemical Properties for Antibody Drug Conjugates and Their Impact on Stability
- An article about how payload conjugation modifies the properties of mAbs and then the impact upon ADC stability

Engineered collagen-binding serum albumin as a drug conjugate carrier for cancer therapy
- Researchers are looking at using a serum albumin carrier conjugated to a collagen-binding domain which is in turn conjugated to a pH-labile Doxorubicin payload.  Its a novel approach to an ADC and is showing some success in mouse models

Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting DM1 Drug Conjugates
- I love seeing all of the work on the linkers.  They are so often left on the sidelines of the discussion but their manipulation can have a significant effect on therapeutic index.  Here the team was looking to decrease hepatic uptake through linker modifications

Reports -

Clinical Results -
Dr. Bhave Discusses [Fam-] Trastuzumab Deruxtecan in HER2+ Breast Cancer
- Dr. Bhave talks about the steady progression of Daichii's progress through the clinic as well as the competition with T-DM1

Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study
- Chalk another win up for SeaGen and Adcetris.  The combination therapy is showing good results with an ORR of 73% and a full remission rate of 37%.  Not too shabby

The evolving role of trastuzumab emtansine (T-DM1) in HER2-positive breast cancer with brain metastases
Critical Reviews in Oncology/Hematology
- Here is a nice review of Kadcyla in patients with brain metastases.  Apparently HER2 overexpression isn't just a positive indication for Kadcyla, but it also comes with an increased chance for brain metastases.  And, as we know, ADCs cannot get beyond the blood-brain barrier to be effective.  However, despite this, Kadcyla has proven partially effective in these patients.  Maybe the reason isn't clear, but it is definitely interesting

Other - 

Pig to human heart transplants 'possible within three years'
The Guardian
- This is just really cool.  I also like how their microRNA treatment was able to restore heart cells damaged from the heart attack to"almost complete recovery" after a month, but then follows that up with, "most of the treated pigs died after the treatment because the microRNA-199 continued to be expressed in an uncontrolled way."  Oops

Thats it for today. There are always more coming down the pike. Is there something I missed? Contact me.
- - - [Main]

Wednesday, August 7, 2019

ADCDaily - Aug 7th, 2019 - 5 Things in ADCs this Week

Hello again everyone,

It's time again for another update on the world of ADC. There's been lots of good stuff happening as always in our industry and I'm excited to put some highlights below for you to take a look at.
But before we start with that, I have been working on making it easier to get these updates to you without completely relying on you checking your LinkedIn feed. So if you are interested, I have set up an email newsletter service through my blog site.

So if you want to sign up, click on that box on the left hand column of this page.

And lastly, thank you again for taking the time to read these articles. It seems like I wasn't the only one feeling like an ADC news roundup would be useful. So if you like these and want more, please like, comment, or reshare them because every time you do, it makes it that much easier for me to convince my boss that this is a worthwhile use of my time. And now, on to the good stuff...

1. Video of ADC killing mouse cells

Ok, I know that I already shared this on LinkedIn, but it is just that cool. I have watched this video dozens of times. And when the cells explode like balloons it's just too cool. Maybe this isn't the newsiest thing, but it definitely will add some pep to your step when you get into lab next.

Drug Discovery (Source website)

**Side note: I've also watched the video while only looking at the left side of the screen, and that alone is still amazing.

2. New Frontiers in ADC Development

This article is a bit of a longer read, but this is what happens when you get a bunch of the strongest voices in ADCs together to talk about their industry. Tons of good insight and predictions. A realistic look at the industry today as well as some thoughts on where the industry has failed to meet expectations. The article isn't short, but is worth the time for sure.

The article is great, but some of my favorite insights are:
  • When asked what successes ADCs have had, Chris Martin (ADC Therapeutics CEO replied, "Great drugs are built on the shoulders of good drugs, and the progression over the last five a testament to this."
  • The author asked the panel what are ADCs biggest challenges going forward, and it was fascinating to see how different and varied every answer was depending on their backgrounds and current roles.
  • And when asked what the future holds, the responses ranged from new combination therapies, and payload/linker technologies, to non-oncology applications and expansion of the current marketing authorizations.
3. A pair of articles for my fellow ADC nerds out there

There were two articles that I came across that got my mind running. The first is a comprehensive report of the application of different mass spec technologies to ADC characterization.

To be fair, as a process guy, I don't really understand all of the specifics and nuances that this article covers, but I can tell this is something worth taking a look at for anyone who can properly spell Triple Quad LC-MS/MS

The second article is actually a white paper put out by Innate Pharma trying to sell some aggregation standards.

The short version is that they used their aggregate standard to test a bunch of different conjugates. The cool part is where they were able to use the Temperature of Aggregation (Tagg) as a proxy for aggregation propensity. The paper looks at this on the final product, but it's also potentially a very cool assay that could be helpful in process development. Has anyone played with this to see how process changes can affect ADC stability? I'd be interested to see how this can apply not only across multiple constructs like they look at, but at different times during conjugation. Specifically, around cysteine reduction.

4. Market Reports

Maybe someone out there can help me with this one. As I spend a significant amount of time each week curating all of the interesting stories that I can find about ADCs I invariably come across an incredibly large number of these ADC Market Reports. Here are some examples from the last two weeks alone:

And I have links to at least 6 more of these. All looking the exact same. All telling the same thing. All announcing great and immense growth in the upcoming years. Each one is published by a different company, but they are all asking for ~$3280 for access to the PDF report. Who is buying these things? And how can there possibly be so many? Maybe this is the Pharma market equivalent of the Nigerian prince who wants you to hold onto his money for him.

5. Other Links

This is the first article in this edition of the journal Drugs. It is the science journal version of a montage on the approval of Polivy. So if you want to see the entire package wrapped into a nice little story, look no further.

 I know this isn't about ADCs, but if you're like me, you spend an extraordinary amount of time paying attention to ADCs but only hear tangentially about Gene Therapy and its goings-on. So, for those of us who aren't as informed as we might like, the New England Journal of Medicine put together a fantastic report.

Justin's Thoughts:

Putting together these news summaries has been a lot of fun so far, and there is another idea I have been interested in, but I need your help. Instead of putting together a summary of the latest news, I have been interested in diving a little deeper on a specific topic and trying to put something together that is a little more holistic on one specific area of ADCs.

All of that being said, here is the part where we switch to a choose your own adventure novel. Below are a couple of topic areas I have been thinking about. Vote for your favorite in the comments section below, and I will get working on writing up the winner. And as a second check that this is actually interesting to anyone, I'll say the threshold for a go story will be 20 votes.

Choose Your Own Adventure - Volume 1

A) Epitope Masking as an ADC strategy
B) Non-oncology ADC applications
C) Virtual Companies in the ADC space
D) Other? (Got ideas? Lets hear them!)

Have a great week everyone!

Monday, August 5, 2019

ADC Links - Aug 5th, 2019

Videos -

Antibody Drug Conjugate (ADCs) killing mouse breast cancer cells
-The first link is to a video showing cells being killed by an ADC vs its control sample.  In a world of adding clear liquids to clear liquids with very little payout, this concrete video makes me happy.  The second link is the original article, scroll down a ways and the ADC section is in there

Industry -

New Frontiers in ADC Development
The Medicine Maker
- Really interesting article with an interview from some of the major players in the ADC space.  Very long, but also very good with lots of insight into yesterday, today, and tomorrow

Antibody-drug Conjugate Market Top key Players, Size, Share, Demand, Opportunities And Forecasts To 2025
Antibody Drug Conjugate Market Size Is Estimated To Grow at a CAGR of 19% Till 2023 | Industry Trends, Key Players and Global Market Analysis By MRFR
Global Antibody-Drug Conjugate Market Size & Growth by 2019-2024: Companies, Opportunities, Challenges, Growth, Countries, RevenueAntibody Drug Conjugates (ADCs) Market Size: Analysis and In-depth Research on Industry Size, Trends, Emerging Growth Factors and Regional Forecasts to 2025
Antibody Drug Conjugates (ADCs) Market Sales Volume by Global Industrial Growth Rate, Size, Shares, Productions, Demands and Supply Analysis from 2019
Global Antibody-Drug Conjugate Market Size Forecast by 2019-2024: Applications, Geographic Regions, Opportunities, Challenges, Drivers
Antibody Drug Conjugate Market to Experience Significant Growth During the Forecast Period 2018-2025
- Can anybody explain to me why these reports exist?  And how can there possibly be twenty different companies all doing the same research and reaching the same conclusions.  There are at least 5 of these per week, and I just don't understand how there can be that many, and for the low low price of $3280 for an online PDF.  What am I missing?

Weekly Research Analysts’ Ratings Updates for Sutro Biopharma (STRO)
Mayfield Recorder
- In case you wanted to see what happens in the world of cash that flows around the science.  This is a neat little timeline of the Sutro investment ratings.  At some point, I have to wonder if Zachs Investment is just pushing recommendations around to make their customers feel like something is happening.  How can they change their rating on Sutro 5 times in two months

Polatuzumab Vedotin: First Global Approval
- Polivy is live and approved.  Here is a nice summary of its journey to get you up to speed

Single‐Use Technology in Biopharmaceutical Manufacture, Second Edition
Wiley and Sons
- Single-use is all the rage in ADC manufacture these days, take a look at Ch 27  Progress in the Development of Single-Use Solutions in Antibody-Drug Conjugate Manufacturing for the good stuff

Regulatory -

Aetna and Anthem will now pay for more kids with a devastating rare disease to get a $2.1 million drug, reversing earlier denials
Business Insider
- People said that $2.1M was too expensive for a drug treatment.  That insurance companies would never cover such a thing.  But here you have Novartis' Zolgensma doing just that.  Curing disease is a powerful thing, and with the pictures of cute kids behind it, the insurance companies will come around eventually.  This is good news for ADCs as well as they aren't cheap by any stretch either

- I can't claim to have any great insights into the world of FDA regulation within Clinical Trials, but in case any of you do, they just released a new recommendation document

Manuscripts -

Combination Treatment with an Antibody–Drug Conjugate (A1mcMMAF) Targeting the Oncofetal Glycoprotein 5T4 and Carboplatin Improves Survival in a Xenograft Model of Ovarian Cancer
Targeted Oncology
- This is a pretty unique application of ADCs to prolong progression-free survival.  They are working in combination with platinum-based chemo to target an antigen which becomes expressed as an early sign of disease recurrence

Methods in Molecular Biology
- Take a look.  If you are involved in the science of ADC conjugation, then this will be interesting

Investigation of Antibody-Drug Conjugates by Mass Spectrometry
Advancements of Mass Spec in Biomedical Research
- Put your nerd hats on, this is a deep dive into Mass Spec and its application to ADCs

Prediction of Aggregation Propensity and Monitoring of Aggregation of Antibody-Drug Conjugates (ADC) using ProteoStat® Reagents
Drug Target Review
- This is a white paper put out by Innate Pharma.  But it's also potentially a very cool assay that could be helpful in process development.  Has anyone played with this to see how process changes can affect ADC stability?  I'd be interested to see how this can apply not only across multiple constructs like they look at, but at different times during conjugation.  Specifically around cysteine reduction

Reports -

Gene Therapy
New England Journal of Medicine
- I know this isn't about ADCs, but if you're like me.  You spend an extraordinary amount of time paying attention to ADCs but only hear tangentially about Gene Therapy and its goings-on.  So, for thos of us who aren't as informed as we might like, the New England Journal of Medicine put together a fantastic report

Clinical Results -

Phase I safety and pharmacokinetics study of rovalpituzumab tesirine in Japanese patients with advanced, recurrent small cell lung cancer
Lung Cancer
- Rova-T is not dead yet.  Well, to be fair, I don't know.  But at least this report says that Japanese patients exhibited tolerable toxicity and saw partial response rates of 17%.  They conclude that this is worth further investigation, but that doesn't necessarily mean there will be

Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy
- SeaGen keeps rolling with a 44% objective response rate in their pivotal trial.  They are getting closer and closer to bringing their second wholly owned ADC asset

Thats it for today. There are always more coming down the pike. Is there something I missed? Contact me.
- - - [Main]