Castilho Leda R., Moraes Angela Maria (Ed.) Animal Cell Technology: From Biopharmaceuticals to Gene Therapy

Подождите немного. Документ загружается.

exceptions. For example, in Brazil living things (or parts thereof) are not

patentable, except transgenic microorganisms (Art. 18, III). The majority

of countries, however, follow the European example, where only varieties

of plants and animals are not eligible for patent protection.

In Brazil, for instance, the recombinant form of molecules such as IFN-

alpha and human erythropoietin can be patented, as well as the processes

for obtaining them using animal cells. However, the natural forms of these

molecules, as well as the animal cells used to obtain these molecules, are

not patentable.

15.6 Industrial property and technology transfer ofﬁces

The search by the business sector for new sources of technology and the

avidity of universities for new sources of funding have started to give a

new face to some academic environments. Academic–business relations

take many forms: investment of companies in complete projects or parts

of projects, licensing for exploitation of patents, among others.

In whatever form, a company will be much more willing to fund

research if there are guarantees that the technology will not wind up in the

public domain, and will instead receive adequate patent protection. In the

United States, where these movements began to gather steam in the 1970s,

universities had to prepare themselves to deal with these new questions.

On the other hand, the US Government found that the research ﬁnanced

with public funds often wound up on the ‘‘shelves.’’ This prompted the

need for legislation, which culminated in 1980 with passage of the Bayh-

Dole Act. This act authorizes universities and small companies to retain

the patent rights that result from research funded by the federal govern-

ment.

As an indication of the effect of the Bayh-Dole Act, before 1980 fewer

than 250 patents a year were issued to American universities. In 2004, a

survey conducted by the Association of University Technology Managers

indicated that 4458 new licensing agreements were signed that year, and

the number of patent applications ﬁled by universities was 13 021. Be-

tween 1991 and 2004, the survey reported an increase of over 100% in

patent ﬁlings, as well as a 142% jump in the number of licensing and

option agreements signed. These option agreements permit a company to

acquire the right to evaluate a technology for a given period, called the

option period, before deciding whether or not to actually license it.

The survey also found, however, that universities and research institu-

tions need to be patient and should not expect millionaire returns in short

time-frames, since the generation of revenues from licensing is not im-

mediate. Fewer than 1% of the 20 968 licenses active in 2000 generated a

million dollars or more. Of the institutions responding to the survey, only

10% reported proﬁt greater than 20 million dollars from licensing, and

80% of these licenses had already been in force for at least 10 years.

In academic environments, the establishment of industrial property and

technology transfer ofﬁces has arisen from the increased activities to

protect inventions, the need to transfer technologies to enable their

production, and from legal requirements for obtaining patents, all driven

384 Animal Cell Technology

by the search for proﬁts from research and development investments

through commercialization of the technologies patented.

In Brazil, researchers have started to wake up to the need to patent their

inventions, albeit tardily and slowly. The number of patent applications

ﬁled with the INPI (Brazilian PTO), even though small compared with

the number of journal publications and conference proceedings, is increas-

ing every year. Of the 22 000 applications ﬁled in 2001, 6200 were by

Brazilians. In 2000, Brazilians ﬁled 5800 of the 20 000 applications with

the INPI.

Besides seeking assistance from a qualiﬁed professional, researchers

from some institutions in the country can call on specialized units at their

institutions to support and guide them. Among the institutions that have

established such units are Embrapa, Fiocruz, Unicamp (Campinas/SP),

University of Sa

o Paulo, Minas Gerais Federal University, Rio de Janeiro

Federal University, and Rio Grande do Sul Federal University, among

others. The Sa

o Paulo State Research Support Foundation (Fapesp) main-

tains a Patent and Licensing Unit (Nuplitec) to guide researchers whose

projects are ﬁnanced by Fapesp.

In 2004, Law 10,973 was enacted, called the Law of Innovation, which

among other provisions, requires public-funded scientiﬁc and technology

institutions to have an innovation unit to encourage patenting and licen-

sing of technology. This is an important instrument to protect the

intellectual property generated at these institutions, as well as the negotia-

tion for licensing and transfer to the market. Before negotiating with

prospective partners, it is necessary to sign a conﬁdentiality agreement

between the parties to preserve the secrecy of the information exchanged

during the negotiating phase. All this guidance and support is the respon-

sibility of the internal intellectual property and technology transfer ofﬁce.

According to Chamas (2001), although the debate and interest in

intellectual property rights have arrived tardily in Brazil, the legal barriers

are gradually being removed and the climate is becoming more receptive

to the new activities. In this sense, the move by Brazilian universities is

evident to protect and exploit their intellectual property. A portfolio of

patents and similar assets should be the object of a competent business

policy, including frequent analysis of the advisability of commercializing

scientiﬁc ideas. The construction of an ample portfolio of intellectual

property rights is justiﬁed to protect and reward scientiﬁc effort and allow

a period of protected commercialization. Nevertheless, in the case of the

public sector, this may not be the only motivation, since concern must be

given to the country’s social welfare and economic development.

Mention must also be made of the crucial role of support agencies for

the structuring and consolidation of these internal ofﬁces.

An article by Kingston (2000) reports the history of the ‘‘antibiotics

revolution’’ and how the discovery of Pasteur in 1877 that certain bacteria

were able to inhibit the growth of anthrax organisms supplies important

lessons for economic innovation. According to the article, questions such

as the establishment of strategies for patenting and ownership of intellec-

tual property, cooperation between universities and industries, and the

role of support agencies must be considered when seeking successful

innovation of a product/process.

Intellectual property 385

The distinction between the proﬁle of an inventor and innovator is quite

clear from the report involving the invention and innovation of penicillin

and streptomycin. According to Schumpeter (1988), an inventor produces

ideas, while an innovator makes things happen, and materializes ideas.

Personal commitment and willpower are characteristics of an innovator.

This is the difference between Fleming and Florey in relation to the

discovery and innovation of penicillin, respectively. The researcher/inven-

tor has to deal with resistance to new ideas without the ability to make

these new ideas accepted. In contrast, an innovator has the ability neces-

sary to promote ideas and transform them into reality.

Researchers need to be capable of perceiving that an experiment may

generate more information than it is possible to foresee before starting.

On this point, Kingston (2000) shows the misleading effect that a partial

success can have, which he exempliﬁes by the fact that Fleming was only

able to perceive a limited use of his discovery of penicillin, allowing this

partial success to mask the possibility of its use as an antibiotic.

This is where the innovator comes in, capable of noting this previously

unidentiﬁed potential, and especially knowing how to use his or her

personal characteristics to ﬁnd the means to overcome difﬁculties and

convince others to invest in developing and materializing the idea.

15.7 Patent and technology transfer specialists

An internal intellectual property and technology transfer ofﬁce will have

two types of professionals: the industrial property specialist and the

technology transfer specialist. These activities require speciﬁc qualiﬁca-

tions and extensive training, involving expertise normally not mastered by

scientists. For this reason, the interactions between universities and re-

search institutions on the one hand and companies on the other regarding

patenting and marketing of inventions warrant speciﬁc handling.

The intellectual property specialist, usually with a professional back-

ground in engineering, chemistry, physics, or biomedical sciences, needs

to have an understanding of international law, treaties, and conventions as

well as national laws, decrees, edicts, etc., and the entire bureaucratic

apparatus in the ﬁeld. He or she must also interact with scientists to obtain

the information necessary to draft the patent application, study the state of

the art to prepare the diagrams, determine the scope of claims, see to the

deposit of biological material with an international depositary authority,

develop patenting strategies, deal with industrial property agents, follow

the progress of the application, see to maintenance of patents already

granted, monitor the patents and applications of competitors, contest

negative opinions from patent ofﬁces, and respond to the various technical

and legal demands involving the whole process, including any violation of

intellectual property rights (Chamas and Mu

ller, 1998).

Regarding monitoring patent applications of third parties, Brazilian

legislation allows any interested party to submit documents and informa-

tion during an application process period, to assist the technical examina-

tion. This is provided in Article 31 of the Industrial Property Law, and can

be done up to the ﬁnal examination. The tools for this are the Industrial

386 Animal Cell Technology

Property Review and the INPI site. Once a patent has been granted, no

appeal is possible, but administrative cancellation can be sought within 6

months. Court action to nullify a patent can be taken at any time during

its lifetime.

Technology transfer specialists, in contrast, are more focused on busi-

ness aspects. They need to be able to work closely with and understand

the work of the industrial property people, to help them check on the

patent applications ﬁled by the institution. But they also, and more

importantly, must follow market trends involving the portfolio of patents

and applications, orient the preparation of technical cooperation, detect

and contact potential partners for future technology transfers, negotiate

and draft contractual instruments applicable to each case, monitor the

partnerships formed, deal with external law ofﬁces specializing in intellec-

tual property, and act in cases of breach of contractual clauses. In relation

to this last item, when a contractual infraction or other compliance

problem is noted, a choice must be made as to what action to take. Will it

be by judicial action or some form of alternative dispute resolution?

There is a range of alternative dispute resolution (ADR) methods.

Among the most common are arbitration and mediation, although con-

ciliation and direct negotiation are also possible.

Dispute resolution is an important process for business, since it permits

a quick, fair, and economic way to solve conﬂicts, without the need for

prolonged litigation. Hence, it is possible to obtain a more satisfactory

outcome and often to preserve a suitable commercial relationship.

Some activities need to be carried out jointly by the industrial property

and technology transfer specialists. An example is the decision on whether

or not an invention is patentable, or should be patented, based on technical

and economic considerations, and industrial property policies.

Some aspects of intellectual property that need to be evaluated by these

specialists when analyzing a research project are listed below (Mu

ller,

2003).

(i) Searching for prior art and verifying the satisfaction of patentability

requirements.

(ii) Conﬁrming with inventors the absence of disclosure of the result of

the research, even in articles submitted for publication.

(iii) If the patentability requisites are met, preparing the ﬁrst draft of the

application from the technical information sent by the inventors.

(iv) Whenever possible, including functional equivalents of the invention

to enlarge the scope of the protection.

(v) In parallel, conﬁrming who the inventors are and to what companies/

institutions they belong.

(vi) In the case of external inventors, verifying if there is a formal partner-

ship agreement.

(vii) If so, verifying whether the agreement contains ownership clauses.

(viii) Identifying the percentage of intellectual contribution of each inven-

tor in materializing the invention, information that will inﬂuence the

percentage that will accrue to each company/institution.

(ix) Verifying whether there were or will be other external sources of

Intellectual property 387

funding for the project besides the outlay of the company/institution

itself.

(x) Whenever possible, negotiating the ownership of the company/insti-

tution and proposing an agreement between the parties stipulating

the percentage that belongs to the other party or parties as a result of

commercial exploitation of the invention.

15.8 Conclusions

Based on the above observations, the importance of patent protection of

biotechnology inventions is clear, as well as the need for professionals

trained to take care of the protection and licensing of the intellectual

property generated by universities, research institutions, and companies.

Public–private partnerships should be encouraged as essential for the

development of products and processes, and especially to leverage invest-

ment seeking to reduce the dependence on imported biopharmaceuticals.

For this, it is vital that institutions adequately project their research results,

to enable them to better attract investors to fund technological develop-

ment. Hence, it will be possible to increase the chances that an invention

will turn into an innovation.

References

Association of University Technology Managers (1999), AUTM Licensing Survey FY

1996. Norwalk: AUTM.

Beier FK, Straus J (1986), Genetic engineering and industrial property, In: The

Sixteenth Bitburg Colloquium on Genetic Engineering and Law, Bitburg,

Abstracts.

Bull AT, Holt G, Lilly MD (1982), Biotechnology: International Trends and Perspec-

tives, OECD, Paris.

Chamas CI (2001), Protec¸a

o e Explorac¸a

o Econoˆmica da Propriedade Intelectual em

Universidades e Instituic¸o

es de Pesquisa, COPPE/UFRJ, PhD Thesis.

Chamas CI, Mu

ller ACA (1998), Gereˆncia da Propriedade Industrial e da Transfer-

eˆncia de Tecnologia, In: XX Simpo´ sio de Gesta

o da Inovac¸a

o Tecnolo´ gica, Sa

Paulo, Abstracts.

Gama Cerqueira JDA (1982), Tratado da Propriedade Industrial, 2nd Ed., Editora

Revista dos Tribunais, Rio de Janeiro.

Kingston W (2000), Antibiotics, invention and innovation, Research Policy 29:

679–710.

ller ACA (2003), Patenteamento em Biotecnologia: Abrangeˆncia e Interpretac¸a

ode

Reivindicac¸o

es, EQ/UFRJ, PhD Thesis.

Schumpeter JA (1988), A teoria do desenvolvimento econoˆmico, Nova Cultural, Sa

Paulo.

388 Animal Cell Technology

Recombinant therapeutic

pr oteins

Maria Candida Mai a Mellado and Leda dos Reis Castilho

16.1 Introduction

Biopharmaceuticals are proteins and nucleic acid-derived molecules that

are used for therapeutic purposes or in vivo diagnostics, and are produced

by means other than direct extraction from a native (non-engineered)

biological source (Walsh, 2002). When considered together with vaccines

and biomolecules extracted from natural sources, they are designated

‘‘biologicals’’ by the pharmaceutical industry.

A survey carried out by the Pharmaceutical Research and Manufacturers

of America (PhRMA) veriﬁed that in 2004 over 100 biopharmaceuticals

had already gained approval from the US Food and Drug Administration

(FDA) (PhRMA, 2004). This survey found that 324 new biotechnology

medicines, targeting nearly 150 diseases, were undergoing human clinical

trials or under review by the FDA. Among the products under develop-

ment, almost half (154) were intended for cancer treatment, and another

signiﬁcant portion for infectious diseases, AIDS/HIV and related condi-

tions, and autoimmune and neurological disorders. Despite the long

development time for biopharmaceuticals (Figure 16.1) and the fact that

most molecules under clinical trials do not gain ﬁnal approval from the

regulatory agencies, a considerable increase in the number of commercia-

lized biopharmaceuticals is expected in the next few years.

It is estimated that to date more than 250 million people worldwide

have beneﬁted from the biologicals already approved for the treatment or

prophylaxis of cardiac diseases, multiple sclerosis, several types of cancer,

hepatitis, arthritis, and diabetes, among others. Since biopharmaceuticals

focus their action on the molecular basis of diseases, they are providing

physicians and patients with new powerful tools for the treatment of

diseases, changing fundamentally the way diseases are treated (PhRMA,

2004).

16.2 Main therapeutic proteins

Therapeutic proteins can be divided into seven different groups: cytokines,

hematopoietic growth factors, growth factors, hormones, blood products,

enzymes, and antibodies (Walsh, 2003). Most of these proteins have

complex structures and undergo different post-translational modiﬁcations,

such as glycosylation, which usually is essential for biological activity, as

discussed in Chapter 6. For this reason, most of the biopharmaceuticals

already approved or under development are produced by mammalian cells,

since microorganisms and insect cells are not able to correctly perform the

required post-translational modiﬁcations. Among mammalian cells, the

cell line most usually employed in the production of recombinant ther-

apeutic proteins is the CHO cell line (Chinese hamster ovary cells), which

provides proteins with a glycosylation pattern very similar to that of

human native proteins. Besides, CHO cells are considered safe because the

major viruses that cause disease in humans are not able to replicate in these

cells. The manufacturing processes for these proteins are all based on

principles discussed in the previous chapters of this book.

16.2.1 Cytokines

Cytokines play a central role in regulating the immune and inﬂammatory

response. Interferons (IFNs) were the ﬁrst family of cytokines to be

CommercialPhase IIIPhase IIPhase I

IND

Duration (years)

Develop-

ment

phase

123

Preclinical

Phase I

Phase II

Phase III

BLA

Phase

Premises

Expression

system

defined

Process

scalability

Primary

definition

of process

validation

Refinement of

operational control

parameters

Development of

scale-down process

models for validation

Process out-of-limit

definition

Finalization of

process control

parameters

Fixed and defined

process and

products

Pivotal process

validation and

characterization

studies

Validated

production

process

Well-characterized

product

Robust process

Figure 16.1

Phases in the development of a biopharmaceutical and the concept of time-to-market. IND,

Investigational New Drug Application; BL A, B iologics License Application

(adapted from Werner, 2004).

390 Animal Cell Technology

discovered, and are used as biopharmaceuticals to enhance the immune

response against infectious agents (viruses, bacteria, and protozoa) and to

treat some autoimmune conditions and some types of cancer (Table 16.1).

There are distinct classes of IFNs, and humans produce at least three;

IFNÆ, IFN, and IFNª (Walsh, 2003).

The IFNÆ class consists of approximately 20 subtypes of mole-

cules, most of them having 165–172 amino acids and a molar mass of

approximately 20 kDa. Depending on the subtype, they can be either

O-glycosylated or non-glycosylated, and present over 70% amino acid

homology with each other. Beyond being abundant in leucine and gluta-

mate, they are characterized by conserved cysteines, usually at positions 1,

29, 99, and 139, which generally form two disulﬁde bonds. The secondary

structure is characterized by several Æ-helices and no -sheets. The major

application of IFNÆ as a biopharmaceutical is the treatment of hepatitis,

but some commercial preparations have already been approved for leuke-

mia and other types of cancer.

IFN is produced in vivo normally by ﬁbroblasts. In humans, only one

IFN is found, which has 166 amino acids and a molar mass larger than 20

kDa. The molecule has a disulﬁde bond as well as an N-linked carbo-

hydrate chain bound to asparagine 80. Structurally, it is characterized by

the presence of ﬁve Æ-helices. Recombinant IFN is marketed under the

names of Betaferon

, Betaseron

, Avonex

, and Rebif

, being indicated

for the treatment of multiple sclerosis, since it blocks the secretion of other

cytokines involved in the pathogenesis of this disease.

IFNª, also known as immune interferon, is produced in vivo predomi-

nantly by lymphocytes. Human IFNª has 143 amino acids, with a molar

mass varying between 17 and 25 kDa, depending on the level of N-

glycosylation. The secondary structure consists of six Æ-helices. The most

important therapeutic application of IFN ª is the treatment of chronic

granulomatous disease (CGD), a rare genetic condition characterized by

the deﬁciency of phagocytic cells. CGD is characterized by repeated

infections in sufferers because of the absence of phagocytes to ingest or

destroy infectious agents (Walsh, 2003).

Until the 1970s, the source of exogenous IFN for therapeutic use was

human blood itself. However, recombinant DNA technology made possi-

ble the cloning of IFN genes into several expression systems, such as

Escherichia coli, yeast, and mammalian cells, facilitating the large-scale

production of these proteins and increasing safety. The level of glycosyla-

tion of these proteins determines the expression system in which they

should be expressed. IFNÆ, for example, is not glycosylated in its native

form and therefore can be expressed in E. coli. Mammalian cells, especially

CHO cells, may be used to produce the other IFN classes, which are

glycosylated.

Another cytokine class used as a biopharmaceutical is interleukin (IL),

which consists of at least 25 different subtypes (IL-1 to IL-25). Except for

IL-1, most interleukins are glycosylated and have a molar mass in the

range of 15–30 kDa. IL-2 is the most well studied interleukin, and its

recombinant form is approved for the treatment of renal cell carcinoma.

Since the absence of glycosylation does not affect its biological activity,

rIL-2 is produced in genetically engineered E. coli.

Recombinant therapeutic proteins 391

16.2.2 Hematopoietic growth factors

Hematopoietic growth factors are also cytokines and play an essential role

in the formation and differentiation of blood cells (hematopoiesis). The

main molecules of this family are erythropoietin (EPO), granulocyte

colony-stimulating factor (G-CSF), macrophage colony-stimulating factor

(M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-

CSF).

GM-CSF, also known as pluripoietin-Æ, is a glycosylated polypeptide

with 127 amino acids and a molar mass of approximately 22 kDa. The

secondary structure exhibits four Æ-helices and two anti-parallel -sheets.

G-CSF (or pluripoietin) is a glycoprotein with two splicing variants, the

predominant one presenting 174 amino acids and 21 kDa, with only one

O-glycosylation site. Its structure is characterized by the presence of two

disulﬁde bonds and four Æ-helices. M-CSF (or CSF-1) has three N-

glycosylation sites and several disulﬁde linkages. There are three forms of

this protein, with molar masses varying from 45 to 90 kDa and the largest

one having 522 amino acids (Walsh, 2003).

The three types of recombinant CSFs (GM-CSF, G-CSF, and M-CSF)

are used as hematopoietic stimulators, in the treatment of infectious

diseases, some types of cancer, bone marrow transplants, and neutropenia,

a disease characterized by a reduced level of neutrophils, the precursors of

white blood cells (Table 16.1).

EPO is a globular glycoprotein, characterized by four Æ-helices and two

anti-parallel -sheets, which contains 166 amino acids. It has a molar mass

between 34 and 40 kDa, 40% of which is due to carbohydrate chains. The

molecule has three N-glycosylation sites (asparagine residues 24, 38, and

83) and an O-glycosylation site (serine 126). The carbohydrate chains

contribute to the solubility, in vivo metabolism, and cellular processing of

the molecule. However, its complex glycosylated tetra-antennary structure

and the high degree of sialylation enhance the importance of a careful

control of operational conditions during the manufacturing process. This

aims at minimizing the micro- and macroheterogeneity and, consequently,

maximizing the yield in terms of isoforms with high biological activity

(see Chapter 6).

The ﬁrst approval of a therapeutic use for recombinant EPO was in

1989 for the treatment of anemia related to chronic renal failure. The

treatment with EPO stimulates production of erythrocytes and improves

the patient’s quality of life, as well as reducing or eliminating the need for

blood transfusion. There are other non-renal applications, such as the

minimization of blood transfusion after surgery, the prevention of anemia

after bone marrow transplantation, and the treatment of anemia caused by

the use of antiretroviral drugs, by chemotherapy, and by prematurity.

16.2.3 Growth factors

Apart from the hematopoietic growth factors, discussed in Section 16.2.2

above, there are other types of growth factors, such as transforming

growth factor (TGF), platelet-derived growth factor (PDGF), insulin-like

growth factor (IGF), and epidermal growth factor (EGF).

392 Animal Cell Technology

TGF consists of a family of growth factors employed in the treatment

of bone fractures and skin ulcers. TGF molecules of type  exist in the

form of homodimers of 112 amino acids. Two members of this family have

their recombinant form approved for treating tibia fractures (Osigraft

and InductOs

), being produced in mammalian cells (Table 16.1).

PDGF, which plays an important role in wound healing (cicatrization),

is a dimer formed by two polypeptides. There are two isoforms of this

protein that are most commonly encountered in the human body: one

with 110 amino acids and another with 125. Both isoforms have one

glycosylation site and three disulﬁde bonds.

IGF is a polypeptide of 70 amino acids, with three disulﬁde bonds and a

molar mass of 7.6 kDa. Its therapeutic use is still under study and future

medical applications for this protein are likely to be the treatment of

dwarﬁsm, diabetes type 2, and renal diseases, among others.

EGF has a sequence of 1208 amino acids divided into seven domains,

the largest being a glycosylated peptide of 53 amino acids. The secondary

structure is characterized by the presence of two anti-parallel -sheets and

three disulﬁde bonds, which confer stability to the molecule. This protein

is indicated for the treatment of wounds and skin ulcers.

16.2.4 Hormones

Hormones are proteins responsible for regulating molecular synthesis in

vivo. The most well known therapeutic hormones are insulin, glucagon,

growth hormones, and gonadotropins.

Recombinant human insulin and recombinant human growth hormone,

both produced by microbial cells, were the ﬁrst biopharmaceuticals to

obtain approval from the regulatory agencies. Insulin is widely used for

diabetes treatment, whereas growth hormone is used in the treatment of

short stature, obesity, and for stimulating ovulation.

The gonatropins are a family of hormones that include follicle stimulat-

ing hormone (FSH), luteinizing hormone (LH), and chorionic gonadotro-

pin (CG), among others. These three proteins are heterodimers that

contain an identical polypeptide subunit (Æ) and another speciﬁc subunit

(), which confer the respective biological activity. FSH has a molar mass

of 34 kDa, 14% of it being due to carbohydrate side chains. LH has a

molar mass of 28.5 kDa.

The recombinant forms of these proteins (Gonal-f

, Luveris

Ovitrelle

, and Puregon

), produced in CHO cells, are indicated for

treating female infertility (Table 16.1).

16.2.5 Therapeutic enzymes

There is a great range of recombinant enzymes used for therapeutic

purposes, but not all of them are expressed in mammalian cells.

Tissue plasminogen activator (tPA) is a protease with 527 amino acids

and 4 glycosylation sites that acts in vivo as a thrombolytic agent. Its

function is to proteolytically convert the zymogen, plasminogen, into

active plasmin, which in turn degrades ﬁbrin strands, thus dissolving

the clots (Walsh, 2003). For this reason, recombinant tPA molecules

Recombinant therapeutic proteins 393