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Biosamples storage without refrigeration; Central Europe attractive for vaccine manufacturers; Zika virus for brain tumors treatment; Mechanism of lactoferrin antitumor features

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What has caught my attention in Pharma, Biotech, Biomedicine and Science in the last weeks? Here is a selection of the news, articles, papers, findings, risings, falls as I have read, heard, discussed, been involved in. Very subjective, not pretending to be comprehensive or representative. Just my selection.

  • What if we do not need to store biological samples in refrigerator before analysis ? This would allow to send samples for special analyses to labs even from remoted areas and people could get more adequate diagnosis and subsequently also treatment even in areas without electricity, refrigerators and freezers.
  •  Are Central European countries attractive for vaccine manufacturers? According to the latest news on new or expanded factories, yes. It is only a pity that Slovakia has not yet attracted any such vaccine manufacturer or developer- this can be interesting among other reasons also due to presence of highly qualified people in life sciences in the country and also due to latest rules regarding tax deductions of expenses for R&D and a new “patent box” law affecting positively tax height from patented product sales.
  •  Hard to believe but Zika virus can be in future used to fight brain tumors. It might be that the Zika virus research will instruct people how to defeat the most aggressive tumor types- tumors of CNS.
  •  Slovak and Austrian scientists explain why lactoferrin posses its anticancer features. This protein from human milk inhibits spreading of cancer cells.

 

No need for refrigerating of biological samples- just place it on a filter paper

All people working in the biological field are aware of importance of refrigeration of biological samples as plasma, urine, blood, etc. Rapid destruction of proteins, nucleic acids and metabolites observed at room temperature lead to incorrect and misleading results, sometime even impossibility to analyze a sample. What if there is a technology which can preserve important molecules like proteins in samples in such way that they can be just placed on a filter paper and sent to a laboratory for analysis?

 Researchers at Washington University are developing a method which can remove a need for a cold chain in processing of biosamples. If proven as reliable and robust, it can not only decrease expenses of analyses but it can also contribute to improved access to such analyses of people in remote geographical areas. A notable effect is also a better standardization of the biosamples storage and thus improvement of reliability of subsequent analyses. Researchers “used a nanoporous material to essentially shrink wrap protein biomarkers in blood and urine samples by growing crystals around the molecules. Then, they transferred the shrink-wrapped molecules onto standard lab filter paper. Once dry, the paper can be shipped at any temperature to a lab for testing.”

Central Europe is involved in expansion plans of vaccine companies: A new vaccine plant in Czech Republic and an expanded Hungarian vaccine facility

Through the deal to buy Nanotherapeutics in the Czech Republic (72 mil EU deal), Serum Institute of India will get a former Baxter flu vaccine factory in the Czech Republic. This plant has an ambition to become the largest injectable polio vaccine factory by capacity in the coming years. The investment to get the plant up and running is planned up to 40 mil EUR. Injectable inactivated polio vaccines are according to WHO recommended to be used for vaccination against polio.

GSK is expanding with its vaccines sales and it needs to expand also manufacturing of the vaccines and its components. The Hungarian factory in Gödöllö will be enlarged by the 40 mil GBP investment. The production of diphtheria toxoid and tetanus toxoid will be moved from GSK’s Marburg production site in Germany.

Zika virus can be in future used to fight brain tumors

It is hard to believe that it can be something good on Zika virus in humans. Zika virus infect predominantly neural stem cells and is therefore more harmful to developing fetus than to adult humans. Scientists in Brazil wanted to figure out whether the virus also attack tumor stem cells in the central nervous system (CNS). And they succeeded. By focusing on embryonal CNS tumors, which are very aggressive and which are manifesting shortly after birth or up to adolescence, they showed on tumor cell lines and in cells-induced mice tumors that small amounts of Zika virus is able to infect these cells and in parallel, destroy cells and the cell-induced tumors. The mechanism behind cells and tumors destruction is apparently oncolysis.

In addition, human adult neural cells were neither infected by Zika virus not destroyed at the dose used. Research also suggest that other tumors of CNS like glioblastoma can be also feasible targets for Zika virus-related destruction.

There are of course still more questions than answers but what if such kind of approach can work? This is not of course a first example of an oncolytic virus use for cancer treatment (see e.g the very recent up to $1 Billion deal of Janssen). It might be that the Zika virus research will instruct people how to fight one of the most aggressive tumor types- tumors of CNS.

Protein from human milk inhibits cancer

Plasminogen system belongs to important systems in human organism, above all it removes protein aggregates, especially fibrin clots. If it does not work properly, one can get thrombosis and this can be a life-threatening state. On the other side, as many other molecules in human body, plasminogen is involved in different pathological processes, just to name tumor cells dissemination, neurodegeneration and various inflammatory disorders. Slovak and Austrian scientists found that the human glycoprotein from human milk- lactoferrin- can inhibit plasminogen activation by direct binding to it. Lactoferrin was able to inhibit tumor cells invasion. In addition to that, lactoferrin also inhibited plasminogen activation by a microorganism species Borellia.

Dr. Vladimir Leksa, the scientist at the Molecular Immunology Unit of HAI, CePII, MUW, Vienna, Austria and at the Slovak Academy of Sciences (SAS), Bratislava, Slovakia: “Lactoferrin is a long time known as an immunomodulatory molecule with antimicrobial and antitumor activities. Thus, to use lactoferrin for treatment is not a new concept. It is a milk protein, which makes it biologically safe for such type of studies. Its function as a plasminogen activation inhibitor revealed by us was so far not known and may explain many of its biological activities. According to our data, it targets cell-associated plasminogen activation resulting in inhibition of cell migration, including tumor cell and bacteria invasion. We are planning further mouse experiments to support and explore further the findings”.

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Cell vaccines; AFFiRiS´ PCSK9 and PD vaccines; Pfizer´s smoking cessation vaccine

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This time I will scan selected vaccines against chronic and non-infectious diseases as appeared in my report (available also via this link). There should have been available results from about 20 Phase III to Phase I vaccine trials in 2016. And some interesting clinical trials started in 2016. Again, my selection is very subjective, not pretending to be comprehensive or representative. Just my selection. For more details you can go to my original report or to some of the posts published on my website.

Let´s have a look on 3 vaccine with 2016 milestones. I believe that success of infectious disease vaccines and saving of millions of lives can be translated also into vaccines for non-infectious indications and chronic diseases. In parallel to very complicated underlying basis of chronic diseases (in comparison to infectious diseases), it will be also a technology employed which matters in development of successful vaccines against chronic diseases. So far we have seen a lot of failures in this field. There are however also some optimistic news and still many vaccines in development in biotech, universities and pharma companies.

Algenpantucel-L vaccine against pancreatic cancer
Algenpantucel-L was an advanced cell vaccine in Phase III for treatment of pancreatic cancer in development at the company New Link Genetics. In May 2016 the company announced failure of the vaccine in the Phase III commercialization trial and shortly after that stopped all vaccine developments based on the same technology. They had also other candidates of the same technology in late development- Tergenpumatucel -L/Hyperacute® Lung for treatment of non-small-cell lung cancer (Phase II/III), HyperAcute® Prostate for treatment of prostate cancer (Phase I/II) and the combination vaccine Tergenpumatucel-L+indoximod (checkpoint inhibitor) for non-small cell lung cancer (Phase IB/II).

Algenpantucel-L consisted of 2 modified pancreatic cancer cell lines (HAPa-1 and HAPa-2) that have been modified to express a molecule α-gal. After immunization, pre-existing antibodies in humans against α-gal (which are thought to be a consequence from chronic immunological stimulation) immediately opsonized mouse pancreatic cells. α -gal epitopes are the major target of the hyperacute rejection response. This response occurs when organs are transplanted from lower animal donor species into primates and results in a rapid destruction of transplanted tissue and an augmented response against transplant antigens, including antigens not related to the α-gal epitopes. Such destroyed allogeneic pancreatic cancer cells are then processed by immune cells. Because cancer-specific antigens within the algenpantucel-L are shared by cancer cells in the patient, patient cancer cells were believed to be targeted by the immune system.

New Link Genetics is focused now on their other technology- inhibitors of the indoleamine 2,3-dioxygenase (IDO) pathway with two candidates. One candidate is licensed to Genentech. IDO pathway inhibitors belong to so called checkpoint inhibitors (like PD-1 or PD-L1). PD-1 checkpoint inhibitors Keytruda (Merck) and Opdivo (BMS) are both approved medicines in USA and in EU for more cancer indications.

AFFiRiS´PCSK9 and Parkinson´s disease vaccines
I cannot of course forget the peptide vaccines from my former employer AFFiRiS. Two PCSK9 vaccines AT04A and AT06A have different mode of action on the PCSK9 molecule.

Inhibition of PCSK9 was shown to decrease the “bad” LDL cholesterol (LDLc) which is involved in development of atherosclerosis and cardiovascular diseases (CVD). Two monoclonal antibodies against PCSK9 were approved by FDA and EC in 2015, however the trials to definitely confirm that decrease of LDLc by targeting PCSK9 is accompanied by an improved CVD rate, are still running.

Nevertheless, AFFiRiS PCSK9 vaccines, if they succeed, will have at least two big advantages over the expensive monoclonal antibodies treatment- a much lower price allowing also a preventive approach in a high proportion of population and an easy possibility to combine- e.g with vaccines against other “CVD” targets.

AT04A and AT06A are peptide vaccines consisting of a few amino acids sequences mimicking the original sequences of PCSK9 coupled to the carrier KLH and mixed with the adjuvant Alum. Both vaccines are B-cell vaccines, so the main mode of action is to induce, like normal infectious disease vaccines, antibodies in a body.

Despite the AT04A and AT06A trial should have been already finished in middle of 2016, AFFiRiS has so far not announced any results from this trial. It seems that the company is collecting data also from a “boost” study to provide more solid dataset, especially in the light of the promising results from their PD01A vaccine boost study (AFF008A) for treatment of Parkinson´s disease.

In the PD01A Phase I clinical trial, supported financially also by Michael J. Fox Foundation, “Immune Response was seen in 86% of patients, resulting in an increase of responder rate after boost immunization” and “PD01A-induced Antibodies Preferentially Bind to Fibrilic Alpha-Synuclein (aSyn)” as announced by the company in September 2016.

Pfizer´s vaccine(s) on smoking cessation
The Phase I trial on the PF-05402536 (NIC7-001) and PF-06413367 (NIC7-003) vaccines was already as of January 2016 marked as completed. Preclinical results from these vaccines on mice and primates were published in 2015 and also in 2016. The vaccines had been in the Pfizer´s pipeline still in August 2016 and then in the newest update, they are, or at least the PF-05402536, discontinued.

The PF-05402536/NIC7-001 vaccine was consisting of the NIC7 (peptide) coupled to the carrier molecule CRM197 and mixed with adjuvants Alum (AL(OH)3) and CpG (TLR9 agonist).

There are so far no results available from the Phase I study with the smoking cessation vaccines PF-05402536 and PF-06413367. Pfizer however published in 2016 very interesting results on how “Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier”. Qb-VLP is another carrier/adjuvant which is used, similarly as the CRM197, to induce an immune response by short molecules (haptens) which are normally not immunogenic. Such results showing the big negative effect of the “helping” carrier molecule on immune response against the antigen (which is THE target) can have very pronounced consequences and can be behind certain failures observed in this field.

Pfizer has been one of the few pharmaceutical companies which have vaccines inducing antibodies for treatment of chronic diseases in pipeline. Now, after discontinuing of PF-05402536, the only vaccine of such kind in their official pipeline is the PF-06753512/PrCa VBIR treatment which is a combination of multi-antigen vaccines, monoclonal antibody and a small molecule for treatment of prostate cancer. At least one vaccine in this regimen is a DNA vaccine since an electroporation device is also tested in this trial. Phase I trial is still recruiting patients and results are not expected before 2019. Fate of the Pfizer´s preclinical PCSK9 vaccine is not known to me.

Source: The updated

Attractive unconventional indications for vaccines developers

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Source: The updated

Source: An updated graph from the “Active immunization for unconventional indications” Report on www.martinalutter.com

It is interesting to have a look on activities of drug developers in area of antibody-inducing vaccines directed against non-infectious diseases and some unconventional indications. These vaccines have been in most cases developed so far as treatment vaccines. This is in opposite to infectious diseases vaccines used as prophylactic vaccines. Despite promising late stage candidates, with some very recent failures, there is still no antibody-inducing vaccine approved targeting other than microorganism antigens (i.e targeting self antigens, addiction molecules antigens and others).

As is also observed in other drug development areas, most of the vaccines are focused on different cancer types and among these, predominantly on solid cancers. Here prostate and breast cancer attracted the most attention of vaccine developers, followed by pancreatic, melanoma, non-small cell lung cancer (NSCLC) and colorectal cancer. There are some vaccines which are tested in clinical trials for multiple cancer indications.

The second most developed area is that of vaccines against neurodegenerative diseases, predominantly against Alzheimer’s disease. Despite a lot of immunotherapy (including mAbs and plasma infusions) failures in recent years there are still more than 10 vaccines in active development against Alzheimer´s disease, targeting one of two main molecules thought to be involved- Aβ and Tau. And, there are some other specialties here like a first ever vaccine for Parkinson´s disease targeting α-syn or a vaccine against Huntington’s disease or Multiple system atrophy.

The third most active development is in allergy indications. Most of the vaccine efforts are still focusing on allergen specific vaccines, though the approach is different from the whole allergen hyposensibilization. There are however also attempts to have a general IgE vaccine to be used in all allergies and IgE-related diseases.

Interestingly, people believe that vaccines can help also with different human addictions– for smoking cessation and drug abuse, as is seen from the fairly high number of vaccines in development for these indications. There have been some failures, especially in smoking cessation efforts, however, there are still some vaccines for this indication in development.

Cardiovascular diseases attract the attention of all drug developers. This is no different in the area of vaccine development. Principally there are vaccines in development aiming at treating hypercholesterolemia and hypertension. It will be interesting to observe the fate of the cholesterol-lowering vaccines in the light of recent findings showing no significant effect of the reduction of “bad” cholesterol, induced in that case by a small molecule targeting CETP, on cardiovascular diseases rate.

The 6th most popular area with a lot of activity in vaccine development has been autoimmune disorders. However, there are more stopped vaccine projects than projects in active development at the present time.

All in all, out of 188 vaccines in the report “Active immunization for unconventional indications”, 97 is still as of today in active development.

There were discontinuations of some late stage candidates in recent weeks.

The aim of the above mentioned report is to provide information about vaccines in development for unconventional indications and non-infectious diseases. Further focus is placed on sophisticated antigen(s)-specific vaccines and vaccines where induced polyclonal antibodies are claimed to be the main mode of action. The scope of this report does not include vaccines against microorganisms which are used for non-infectious diseases (e.g. cancer vaccines targeting HPV). Also, the term “vaccine” as used in this report does not mean a monoclonal antibody (mAb) or immunoglobulin (IgGs) infusion.

Vaccines for non-infectious diseases?

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Who is developing antibody-inducing vaccines for unconventional indications like different chronic diseases, addictions, autoimmune and genetic diseases? Are there vaccines which cure or prevent cancer, Alzheimer´s disease,  Parkinson´s disease or Huntington´s disease? Can we decrease high cholesterol and prevent cardiovascular diseases by a vaccine? Can be a cocaine addiction treated by a vaccine? Or can somebody quit smoking by a simple vaccination?

Results from which clinical trials are expected to be available this year? Which indications are the most attractive for vaccine developers? What are the strategies companies adopt for vaccines development? How to define an ideal vaccine composition which enables to induce a strong, effective and long lasting antibody response? What target is the mostly employed when we talk about antibody-inducing vaccines for unconventional indications? What are highs and falls of vaccines development? Do you want to compare target product profiles for more than 100 active vaccine candidates? Which companies and academic institutions are the most active in vaccines development for unconventional indications? What are the technologies behind? Many answers can be found in the report “Active immunization for unconventional indications”.

Vaccines are one of the most important treatments ever developed. Since 1796 when the first vaccine was tested (against smallpox), vaccines have saved millions of lives and many infectious diseases have been eradicated. This is a continuous process.

A traditional vaccine is a prophylactic vaccine which usually induces long-life immunity against exogenous or foreign antigens expressed on microorganisms. Usually, but not in all cases, these exogenous antigens induce a robust immune response where innate and specific immunity is involved. Immunization with weakened or dead microorganisms or their parts which have been made synthetically, protects against diseases caused by them.

Lessons have been learnt from infectious diseases and years ago people started to study vaccines for chronic diseases too, where a new challenge was introduced- inducing immune reaction against the own molecules which were thought to be involved in pathological processes. These own molecules could either be modified or overexpressed in the body or they could simply attain a structure which changed their function from a protective or normal one to a pathological one. What is important is that the body itself is not able to produce an adequate immune reaction to eradicate such overexpressed or modified molecules. There are successful efforts to help the immune system in chronic diseases by passive vaccination- by infusion of monoclonal antibodies. Therefore the way for using vaccines in indications such as cancer, metabolic diseases, cardiovascular diseases and other chronic diseases is laid open.

Furthermore, there are aims to use vaccines to tackle the “over” reaction of the immune system as is seen in allergic reactions. Here, instead of whole allergen hyposensitization being used, which is a long-lasting, expensive and sometimes not a very effective way to prepare an allergic person to be exposed to their allergen(s), new allergy vaccines are developed in a sophisticated way by creating synthetic vaccines with defined allergen antigens inducing an immune response shifting from IgE to IgGs production or vaccines simply targeting IgE itself.

We should not forget efforts made to use vaccines in the fields of human addictions, biological weapons and recently also in genetic diseases.

All these attempts try to use the best from a vaccine approach- a specific and long-lasting effect and the feasibility to treat a large number of the population without exhausting health insurance systems.

It needs to be said that in contrast to infectious disease vaccines, vaccines inducing antibodies and used for unconventional indications within the scope of the report are, with the exception of two of them, intended to be therapeutic vaccines. There is still a long way to go until there will be working prophylactic vaccines which could be used to protect people from diseases such as various cancers, Alzheimer’s disease, seasonal allergy, smoking addition or obesity. Results from therapeutic vaccinations along with intensive biomarker research and an in depth understanding of the etiology of diseases are paving the way for prophylactic vaccines.

The majority of vaccines for unconventional indications are in development in biotech companies and at universities.

There are however also some big pharma companies involved at the moment in active development which indicates that this approach to bring vaccines to unconventional indications has attracted attention also from big pharma players, sometimes with their own experience with vaccines against infectious diseases.

The year 2016 will be quite unique in regards to development of active vaccinations for non-traditional indications within the scope of the report– there should be results available from about 20 Phase III to Phase I trials.