Pullan's Pieces #165  
November 2020

Dear Reader,

This is the last issue of 2020.  We will be back in early January!  

*  We are attending the virtual Biotech Showcase January 11-15th, which we hope can kick off 2021 with a sense that everyone is there! This year, the Seed Showcase offers a great $777 registration for seed-stage companies.  And for others, you can get a $100 discount if you use the VIP code: PullanConsulting2021 when registering.  Register today 

*  We are also signing up for the bargain use of the BIO platform for partnering meetings Jan 11-15th.  $150 per company (more for service providers).  Sign up here

We hope we get deals done by year end and that you all have a lovely holiday season!



In This Issue

  • Linda:  MTAs in Licensing Deals
  • Linda:   ADCs, an infographic
  • Jessica:  What is In Vivo CAR-T
  • Trevor:  Biotech wins 2020
Linda:  MTAs in Licensing Deals

Material Transfer Agreements (MTAs) often come up in the evaluation period before a licensing deal.   

Purpose:  The MTA enables the potential partner to test your drug candidate or technology and boost confidence in the asset.  An MTA can be a powerful aid to a deal.  Everyone always believes their own data!  


1.  The experiments should only be experiments critical to the decision-making.  It is all too easy to get into nice to know experiments, beyond the need to know.  Focus on what is the most important data. 

2. Experiments need to be carefully designed for a positive result.  All the conditions should be considered carefully to enable a robust result. Any unclear result will derail or delay the licensing deal.  

3.  Confirmatory experiments are best.  This enables the greatest certainty that the conditions will lead to a clear positive result. AND it avoids any new IP. 

4.  Put a time limit on the MTA.  Often MTAs are open until the experiments are completed.  But those experiments may never be completed.  And if you do a deal, the other party may not want another company playing with "their new drug".  

4.  Avoid creating any new IP that could be blocking for future work.  Make sure there can be no new broad method of use claims.   The owner of the asset should not be worse off after an MTA than before.   

5.  Exclusivity is rarely worthwhile for the company seeking an out-license.  The payment for exclusivity is generally small and does not sufficiently compensate for tying up the asset.  Competition for an asset is the most powerful negotiating tool.  

6.  You can charge for expensive materials.  

With these thoughts in mind, an MTA may be a big boost to getting a licensing deal done.  

Jessica:   What is the promise of In Vivo CAR-T?

Get In the CAR

By now the concept of chimeric antigen T-cell receptor (CAR-T) therapy, adding antibody recognition to the immune cells,  is fairly ubiquitous in biotech.  These technologies may be categorized as: ex vivo gene therapy, engineered T-cells, or cellular immunotherapy.  The process to generate ex vivo CAR-T cells involves the extraction of cells (typically autologous, from the patient), the introduction of the CAR construct, expansion of the cells, and then the administration of the cells to the patient.  What if we could cut out a whole bunch of those steps and just introduce the CAR construct directly to the patient?  See schematic:


What’s Under the Hood?

There are some fundamental differences between the two technologies:

Ex Vivo

In Vivo


Vector: construct (usually viral vector) designed to deliver CAR


  • Autologous – cells must be collected from patient, engineered, tested, and re-administered
  • Allogeneic – cells from healthy donor are engineered, tested, and stored for use in humans

Vector:  construct (usually viral vector) designed to deliver CAR

Solid Tumor Targeting?

Possible, but there are challenges:

  • Targeting is often tissue-specific
  • Tumor penetration by cells may be challenging; may need co-administration of a check point inhibitor for more permissible environment

Possible, but there are challenges:

  • Targeting is often tissue-specific
  • Tumor penetration may not be necessary as long as construct can get to draining lymph nodes; co-administration of check point inhibitor may be helpful

Clinical Considerations

Complex – need to extract cells from patient and later administer engineered cells back

Simplified – only need to administer the vector construct; side-effects and/or unintended outcomes unclear currently


Cytokine Release Syndrome (CRS) is a major complication associated with CAR-T; switches are being engineered into cells in order to help modulate intensity of responses

It will be difficult to control how many cells become engineered and therefore intensity of the response may not be readily predictable or controllable

On Target/Off Tumor

In cells, can introduce complex engineering initiatives such as knock-down of the endogenous TCR in order to reduce on target/off tumor effects

Difficult to control, other than via the envelope tropism of viral vectors, which cells will be targeted for expression and/or how many cells will be engineered difficult to manage currently

Classic Cars

There has been so much progress with ex vivo CAR-T, surely, we don’t want to switch allegiance (and all investment) just yet. Additionally, In vivo CAR-T is not yet ready for primetime.  At this point, the commercial reality is mostly a theory, or vision, or mission statement.  Let’s first take a look at some of the exciting innovations in ex vivo CAR-T that are currently being developed:

Allogeneic CAR-T:  Ok, we’ve talked about this a few times, so this should surprise no one.  Combining the introduction of a CAR molecule with the knock-down of endogenous TCR can result in a universally applicable CAR-T product (e.g. Precision Bioscience, CRIPSR Therapeutics to name a few).  Alternatively, deriving T-cells from iPSCs can also lead to an allogeneic CAR-T (e.g. Allogene).

Switchable CAR-T:  One of the current challenges with CAR-T-19 is antigen escape; the tumor cells downregulate the CD19 rendering them invisible from the CAR-T cells.  Developers are designing CAR-T technologies for which the targeting moiety can address multiple targets (e.g. Miltenyi, oNK Therapeutics) or cells that are non-targeting with the option to dose patients with the targeting moiety separately (e.g. Calibr, Prescient Therapeutics). 

Alternative CAR:  Recognizing that the immune system involves the coordination of many different cell types, developers are introducing CAR molecules into other cell types such as NK cells (e.g. Nkarta Therapeutics) or 𝛾/𝛿 T-cells (e.g. GammaDelta Therapeutics, or regulatory T-cells (e.g. Quell Therapeutics). 

Non-viral CAR:  Some developers are shying away from viral vector-mediated delivery of CAR molecules.  The motivations for this can stem from a desire to not have the CAR molecule integrate into the cell genome.  Therefore, some developers are introducing CAR molecules via non-viral methods, such as transposons (e.g. Poseida Therapeutics), delivered via transfection methods.

Test Drive

In the EMBO Molecular Medicine study (2018) referenced above and the as well as the follow-up study, In Vivo CAR-T_OncoImmunology_2019, the investigators found that the LV construct could transduce human CD8+ cells (human PBMCs were transplanted in a mouse model).  Further, in the second study, they demonstrate presence and expansion of both CAR-T and CAR-NK in the vector-treated mice.  The CAR-NK population was small (1-2%); however, this small population may have been sufficient to promote the tumor clearance observed.  These studies are interesting and compelling because they suggest that In Vivo CAR-T may be able to accomplish what CAR-T developers have struggled with, which is the transduction of multiple lymphocyte phenotypes in order to mount a comprehensive assault on the tumor.  Even more exciting is that this may be particularly important for successfully addressing solid tumors. 

The main challenges with developing and administering “classic” CAR-T cells are associated with the cells, not the vector.  As evidenced in the table above, the ability to administer the viral vector directly simplifies the drug development, manufacturing, and delivery, but does it also translate into a safe, efficacious, and cost-effective therapy?  The below are some bullets of considerations around promise and challenges of the 2 approaches:



Ex Vivo

  • Proven success in patients
  • Viral transduction happens in processing, not patient
  • Control over which cells are being transduced*
  • Cells can be engineered to knock-out endogenous TCR and/or knock-in added functions such as cytokine expression
  • Manufacturing inconsistencies due to irregular (unhealthy for autologous) starting material
  • Autologous – logistics of scheduling collection, processing, and administration (time may be precious)
  • Allogeneic – products blend multiple technologies which can necessitate more testing, and also higher cost due to complex manufacturing and royalty stacking

In Vivo

  • Simplified manufacturing – just the vector
  • Off-the Shelf – logistics and storage simplified
  • Potential for robust immune response due to potential for multi-clonal expansion of cells
  • Transduction of (unhealthy) cells in situ less traumatic for cells than cell processing first
  • Transduction is happening in the patient
  • Hard to control the cell type and/or number of cells transduced

*Assuming robust cellular selection and processing

The CAR of Tomorrow

There aren’t many companies that are talking about in vivo CAR, but it is likely there are many that have their eye on it.  One In Vivo CAR-T-focused company emerged on the scene earlier this month, Umoja.  We already are seeing new companies like Umoja spinning out from academic centers with an In Vivo approach.  Will this be an emerging trend in 2021?

Trevor:  Biotech Wins 2020

What a year.  Sad for many, strange for everybody. How do we reconcile continued elevated jobless rates with all-time high stock prices, food pantry lines in southern California that were miles long in April with massive demand for mortgages not more than six months later?  Hmph. Reconciliation feels like a big, heavy, difficult word in America today… 

Our industry had a little something to do with the recently punched all-time highs – two vaccines approximating near complete immunity and a host of others not too far behind gave investors the reason(s) they needed to keep buying shares.  Usually, relief rallies happen after a period of continued selling in the markets but this rally has been borne of a different variety – “Vaccines! What a relief…”  Time will tell, of course, but it seems the all-clear has been given for the biotech industry to keep pressing higher having broken out of a 5-year consolidation:



Data in support of the biotech sector’s golden age of innovation (referring readers again to this piece by Sean Harper and Beth Seidenberg of Westlake Village Biopartners) comes by way of Rhodium Group’s update to their brilliant and ongoing US-China Investment Project.  Capital from China has been an increaslingly important resource for biotechs and while cross border investment between the US and China has been declining in aggregate, biotech/biopharma continues to gobble up more of its shrinking pie of both M&A and venture capital:


This chart out of the Q3 2020 Venture Monitor report from Pitchbook and National Venture Capital Association drives the message home that the fuel to fund the golden age of biotechnology is in good supply.


But easy money from the world’s central banks does not = easy capital raise.  Differentiation and efficacy, indeed, differentiated efficacy (e.g. “ours can achieve what others cannot!”) must still be the rule to your strategy.  And be very careful when applying your novel technology to “low-hanging fruit” that’s already been plucked by others.  Investing precious resources to show technological proof-of-concept might leave you with another way to approach a problem that’s been largely solved by others.  If you’ve got something special, put it to the test! 

As we head into the holiday season.  We wish for you and your teams to meet with the greatest success on the grand ambitions you’ve undertaken.

Pullan Consulting (www.PullanConsulting) provides advice and execution for biotech partnering and fundraising, with outreach to partners and investors, help with the shaping of presentations, evaluations and market analysis, preliminary valuations and deal models, and negotiations from deal prep to term sheets to final agreements.      
We have extensive scientific and financial experience, with many deals signed.  Check out the website for more on clients, tasks, CVs, etc.  And don't forget to look at the resources with whitepapers and decks to help. 

Send us an email or set up a call if you want to explore how Pullan Consulting might be of help!     
Linda Pullan                     Linda@pullanconsulting.com 
Trevor Thompson             Trevor @pullanconsulting.com 
Jessica Carmen               Jessica@pullanconsulting.com