Добавил:

Sekretar kiopkiopkiop18@yandex.ru t.me/Prokururor I Вовсе не секретарь, но почту проверяю Опубликованный материал нарушает ваши авторские права? Сообщите нам.

Вуз:

Ростовский Государственный Медицинский Университет

Предмет:

Медицина общая

Файл:

Книга_5703_Библиотеки_им_академика_М_И_Перельмана

.pdf

Скачиваний:

Добавлен:

12.10.2026

Размер:

6 Мб

Скачать

☆

<<< < Предыдущая 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 4142 / 4942 43 44 45 46 47 48 49 > Следующая >>>

Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human

colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995;95(4):1789e97.

Waterhouse P, Penninger JM, Timms E, wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with

early lethality in mice deﬁcient in CTLA-4. Science 1995;270(5238):985e8.

Waterton JC, Pylkkanen L. Qualiﬁcation of imaging biomarkers for oncology drug development. Eur J Cancer

2012;48:409e15.

Weck PK, Apperson S, May L, Stebbing N. Comparison of the antiviral activities of various cloned human interferon-

a subtypes in mammalian cell cultures. J Gen Virol 1981;57:233e7.

Weinbauer GF, Fuchs A, Niehaus M, Luetjens CM. The enhanced pre- and postnatal study for nonhuman primates:

update and perspectives. Birth Defects Res C Embryo Today 2011;93(4):324e33.

Woo S-R, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and

PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res 2012;72(4):917e27.

Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DAA. Phenotypic analysis of the murine CD4-related glyco-

protein, CD223 (LAG-3). Eur J Immunol 2002;32:2255e63.

Xin Y, Bai S, Damico-Beyer LA, Jin D, Liang W-C, Wu Y, et al. Anti-neuropilin-1 (MNRP1685A): unexpected phar-

macokinetic differences across species, from preclinical models to humans. Pharmac Res 2012;29(9):2512e21.

Xu X, Vugmeyster Y. Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of

therapeutic biologics. AAPS J 2012;14(4):781e91.

Yoshizawa K, Oishi Y, Matsumoto M, Nyska A. Ischemic brain damage after ketamine and xylazine treatment in a

young laboratory monkey (Macaca fascicularis). Contemp Top Lab Anim Sci 2005;44(5):19e24.

Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability

changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular

permeability factor antibody. Proc Natl Acad Sci U S A 1996;93(25):14765e70.

Zeng W, Qin S, Wang R, Zhang Y, Ma S, Tian F, et al. PDL1 blockage increases fetal resorption and Tfr cells but does

not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy. Cell Death Dis 2020;11:119e34.

Zhang Y-H, Tian M, Tang M-X, Liu Z-Z, Liao A-H. Recent insight into the role of the PD-1/PD-L1 pathway in feto-

maternal tolerance and pregnancy. Am J Reprod Immunol 2015;74(3):201e8.

Zhang Y, Liu Z, Tian M, Hu X, Wang L, Ji J, et al. The altered PD-1/PD-L1 pathway delivers the ’one-two punch’

effects to promote the Treg/Th17 imbalance in pre-eclampsia. Cell Mol Immunol 2018;15(7):710e23.

Further reading 397

III. Specialty biologics and indications

This page intentionally left blank

Considerations in the development

of pluripotent stem cellebased

therapies

Justine J. Cunningham

, Alexandra Capela

Catherine Priest

and Eugene P. Brandon

REGENXBIO, Rockville, MD, United States;

Vita Ther apeutics, Baltimore, MD, United

States;

Neurona Therapeutics, South San Francisco, CA, United States;

BrainXell

Therapeutics, San Diego, CA, United States

OUTLINE

Introduction 400

Deﬁnitions, regulations, and therapeutic

applications 401

Human embryonic stem cells 401

Induced pluripotent stem cells 403

Regulations 403

Therapeutic applications 406

Other applications: In vitro

toxicology testing and disease

modeling 406

Important early decisions: Chemistry,

manufacturing, and controls 407

Manufacturing process 407

Raw materials 409

Testing 409

Manufacturing scale 409

Critical decisions in cell line selection 410

Cell line characterization 412

Product characterization 413

Pluripotency and the potential for

tumorigenicity 415

Determining a threshold for residual

stem cells 416

Kinetics, chromosomal stability,

differentiation status, and cellular

attributes 417

Potency assays 418

Product lot release speciﬁcations 419

Nonclinical development 419

Principles of nonclinical development 419

Selection of test articl e for nonclinical

studies and key manufacturing

considerations 420

CHAPTER

399

Nonclinical Development of Biologics, Vaccines and

Specialty Biologics, Second Edition

https://doi.org/10.1016/B978-0-443-13344-2.00004-3

and data mining, AI training, and similar technologies.

Justiﬁcation for route and method of

administration for nonclinical studies 421

Selection of animal model(s) and/or

species for nonclinical studies 422

Genetically immunocompromised

models 423

Pharmacologic efﬁcacy assessments 425

Study design, dose selection and

justiﬁcation of pharmacologic

endpoints 425

Pharmacologic mechanism of action 426

Pharmacodynamics and pharmacokinetics 426

Pharmacodynamics 426

Pharmacokinetics (absorption,

distribution, metabolism, and

excretion) 426

Human-speciﬁc markers 428

Reporter genes, edited cells, and Y

chromosomes 428

PET, SPECT, MRI, and

bioluminescence 429

Special considerations for species and

model selection for assessment of

toxicity 429

Safety pharmacology 430

Toxicity assessments 431

General toxicity 431

Reproductive and developmental

toxicity 433

Genetic toxicity 433

Tumorigenicity assessment 434

Local tolerability 435

Translating nonclinical data to clinical

application 436

Considerations for dose extrapolation 436

Clinical considerations and

endpoints 436

Global regulatory guidance 437

Ethical and political issues 437

Clinical studies of PSC-derived

therapeutic candidates 438

Pioneers in translating to human trials 438

Reﬂection on clinical investigations to

date and looking forward 441

Summary 441

References 443

Introduction

Since the ﬁrst description of human pluripotent stem cells (PSCs) in 1998 (Thomson et al.,

1998), there has been tremendous excitement surrounding their potential to transform our un-

derstanding of cell and molecular biology, and to develop treatments for a wide array of dis-

eases with unmet medical need. The scientiﬁc signiﬁcance of human PSCs was recognized

with the Nobel Prize in Physiology or Medicine in 2012 (Park, 2012).

This chapter is intended to provide an overview of key considerations for the nonclinical

development of PSC-based therapeutics. PSCs are cells that are capable of differentiating into

derivatives of all three primary germ layersdendoderm, mesoderm, and ectodermdand

maintain such pluripotency through multiple passages or cell divisions (Thomson et al.,

1998). They can be differentiated into virtually any cell type in the body, although they

can only give rise to a limited range of extraembryonic tissues and cannot form placenta.

12. Considerations in the development of pluripotent stem cellebased therapies400

III. Specialty biologics and indications

Since PSCs can be differentiated into a multitude of cell types, they have the potential to be

applied to a virtually unlimited number of human disease and injury states.

There are two main types of PSCsdembryonic stem cells (ESCs; sometimes called hESCs

to distinguish the human cells from mouse ESCs, for which signiﬁcant data also exist) and

induced pluripotent stem cells (iPSCs). PSC-derived cellular therapies are expected to restore

function or ameliorate disease by two main mechanisms: (1) Replacement of diseased cells/

tissues and/or (2) secretion of factors that support the endogenous environment. It is worth

noting, that CAR-T cells may be derived from PSCs and employ a third mechanism whereby

the expression of the target cell receptor is genetically modiﬁed to bind and then lyse the

target population (Zhou et al., 2022). This application highlights the fantastic versatility of

PSCs, and that the future likely holds many other possible ways they may be utilized and

mechanisms of action. Theoretically, PSC-derived cells can be used at various points in matu-

ration to differentiated progeny, from an early precursor state to a progenitor state, or to a

terminally differentiated state. A recurring theme in the ﬁeld is that determined or committed

progenitors may provide advantages for cell therapeutics as they tend to be more robust and

still retain some modest mitotic potential postadministration, relative to terminally differen-

tiated counterparts.

Adult stem cells have been used therapeutically for decades, starting with hematopoietic

transplants in the 1960s (Thomas et al., 1957; Becker et al., 1963; Thomas and Epstein, 1965;

Buckner et al., 1970). Numerous types of adult stem cells, such as hematopoietic and more

recently mesenchymal stem cells (MSCs), have been identiﬁed and are used clinically for their

regenerative and repopulating properties, paracrine regulatory effects, and immune-

modulatory activity (Krampera et al., 2007). However, adult stem cells are multipotent, not

pluripotent, and can only give rise to tissues of the embryonic germ layer from which they

originate (ectoderm, mesoderm, or endoderm). They also exhibit limited proliferative capac-

ity, diminished differentiation potential and progressive loss of function upon in vitro expan-

sion and with increasing donor age, thus limiting their use in clinical applications (Zhou et al.,

2008; Wagner et al., 2008; Chambers et al., 2007; Bonab et al., 2006; Baxter et al., 2004).

Conversely, PSCs exhibit unlimited proliferation and differentiation potential.

The characteristics that make PSCs such a promising and powerful resource also present

the biggest challenges for nonclinical development and clinical translation. Researchers

must develop new methods to appropriately direct or control cell fate to assure pluripotency

is extin guished, eliminating the risk for potential tumorigenicity. Additionally, the ﬁeld has

recognized that the conditions under which the cells are derived, propagated, and differen-

tiated can impact the genomic stability of the product and therefore the perceived risk for pa-

tients. See Table 12.1 for a comparison of the product attributes of different stem cell-based

therapies.

Deﬁnitions, regulations, and therapeutic applications

Human embryonic stem cells

ESCs are typically derived from the inner cell mass (ICM) of blastocys t stage embryos

(100e200 cells, 4e5 days postfertilization) generated by in vitro fertilization. They can also

be derived from late morula stage (30e40 cells) embryos that are incapable of further

Introduction 401

III. Specialty biologics and indications

TABLE 12.1 Product attributes based on source of cell-based therapies.

Product attributes

Mesenchymal stem

cells

Embryonic stem cells

(allogeneic)

Induced pluripotent

stem cells (autologous)

Induced pluripotent

stem cells (allogeneic)

Pluripotent stem cells

genetically engineered

Source material Bone marrow or

adipose (liposuction)

Blastocyst from IVF

clinic

Skin biopsy or blood draw Same as ESC or iPSC

Proliferative capacity Limited Unlimited

Differentiation

capacity

Restricted (may not

differentiate into cells

that are needed)

Unlimited (need to develop robust and reliable protocol for cell type of interest)

Therapeutic utility MSCs are the

therapeutic candidate

PSCs may be used to make a therapeutic candidate Correction of disease-

associated mutation or

generation of hypo-

immune “universal

donor” cells

Immunologic risk

(implant rejection)

Low (cells are transient

by design with no long-

term effects; MSC are

antiinﬂammatory)

Possible Little to none as the

patient is the donorda

match by deﬁnition

Possible (similar to

allogeneic ESC)

Hypo-immune cells are

designed to reduce or

eliminate need for

immunosuppression

Safety (transmission of

infectious agent(s))

Moderate risk Low risk Low risk Moderate risk Moderate risk

Safety (tumorigenicity) Little concern; cells do

not engraft or persist

Moderate to high

concern; though likely

HLA mismatch to

patient could facilitate

immune detection and

rejection

Moderate to high

concern

Moderate to high

concern though likely

HLA mismatch to

patient could facilitate

immune detection and

rejection

Moderate to high

concern if immune

rejection is not possible

due to genetic

modiﬁcations

Economic feasibility/

advantage

High cost Moderate cost Higher cost due to

longer manufacturing

and QC on each donor’s

batch

Moderate cost Higher cost due to

additional

manipulations and

CMC

Ethical/legal concerns “Stem cell clinics” may

thwart regulation and

cloud bona ﬁde

therapeutic potential

Some jurisdictions Few

Adapted from Cavagnaro (2007).

12. Considerations in the development of pluripotent stem cellebased therapies402

III. Specialty biologics and indications

development, or from single blastomeres dissected from 8-cell embryos. The successful isola-

tion of ESCs was ﬁrst described in 1998 by James Thomson and his team at the University of

Wisconsin, Madison (Thomson et al., 1998). Because they come from blastocysts, hESCs are

always allogeneic.

Induced pluripotent stem cells

iPSCs are adult somatic cells that have been genetically reprogrammed to an embryonic

stem cell-like state by artiﬁcially forcing the expression of genes or factors importan t for

maintaining pluripotency. Human iPSCs were ﬁrst reported in 2007 by Shinya Yamanaka

and his team at Kyoto University, Japan, and were reprogrammed by the transduction of

genes encoding four deﬁned transcription factorsdOct3/4, Sox2, Klf4, and c-Mycdnow

colloquially known as “Yamanaka or OSKM factors” (Takahashi et al., 2007). Yamanaka

was jointly awarded the Nobel Prize in Physio logy or Medicine in 2012 for this innovation

(Park, 2012). iPSCs demonstrate key characteristics of PSCs, namely the expression of stem

cell markers, the ability to form all three germ layers, and the ability to differentiate into

many different cell types. More recently, reprogramming cells to pluripotency has bee n

demonstrated to reset the biological “aging clock” and may hold promise for reprograming

epigenetic rejuvenation (Simpson et al., 2021). In the earliest versions of iPSC reprogramming,

viral vectors were used to deliver the pluripotency transcription factors, and consequently,

older iPSC lines may carry some risk regarding expression of proto-oncogenes and/or inser-

tional mutagenesis (Selvaraj et al., 2010). More recent reprogramming techniques, such as use

of nonintegrating vectors (Yu et al., 2009), recombinant protein transduction (Zhou et al.,

2009), induction using small molecules (Ichida et al., 2009), and synthetic mRNA (Kogut

et al., 2018; Warren and Lin, 2019), avoid some of these risks by creating “scarless” lines

(i.e., with no traces of reprogramming left behind in the host genome), thereby carrying fewer

off-target mutations that may affect the presumed safety of the cells. Because the source ma-

terial can be from the patient themselves, iPSC can be autologous, or if from another donor,

allogeneic.

Regulations

PSC-based therapeutics are regulated by the FDA’sOfﬁce of Therapeutic Products (OTP)

within the Center for Biologics Evaluation and Research (CBER). Table 12.2 provides a list of

regulatory guidances that are applicable to PSC-based therapies. If the cell product is

intended to be used along with a medical device (e.g., matrix, encapsulation device) or a

drug (e.g., growth factors), it would be considered a combination product and therefore could

also be reviewed by the Center for Devices and Radiological Health (CDRH) and/or the Cen-

ter for Drug Evaluation and Research (CDER), respectively. The lead center for regulation

and review of a combination product is dictated by the candidate product’s primary mech-

anism of action (PMOA). If the intended PMOA is not obvious, a Request for Designation

can be submitted to the FDA. The same regulations and recommendations also apply to

iPSC-based products. However, iPSCs might also be considered a gene therapy product if

gene transfer via a vector- (such as a retrovirus, adenovirus, plasmid) based delivery system

was used to reprogram the cells. Regardless of the reprogramming method used, iPSCs

constitute gene therapy products if additional genetic engineering (such as editing) was

used to generate the ﬁnal cell product.

Introduction 403

III. Specialty biologics and indications

TABLE 12.2 Resource documents for pluripotent stem cell-based therapies.

FDA guidances related to cellular therapies

Points to consider in the characterization of cell lines used to produce biologicals July 1993

FDA proposed approach to regulation of cellular and tissue-based products February 1997

Screening and testing of donors of human tissue intended for transplantation; applicable to cells

recovered before May 25, 2005

July 1997

Guidance for industry: Guidance for human somatic cell therapy and gene therapy March 1998

Guidance for industry: Eligibility determination for donors of human cells, tissues and cellular

and tissue-based products (HCT/Ps); applicable to cells recovered after May 25, 2005

August 2007

Guidance for FDA reviewers and sponsors: Content and review of chemistry, manufacturing, and

control (CMC) information for human somatic cell therapy investigational new drug applications

(INDs)

April 2008

Guidance for industry: Considerations for allogeneic pancreatic islet cell products September 2009

Guidance for industry: Cellular therapy for cardiac disease October 2010

Guidance for industry: Potency tests for cellular and gene therapy products January 2011

Guidance for industry: Current good tissue practice (CGTP) and additional requirements for

manufacturers of human cells, tissues, and cellular and tissue-based products (HCT/Ps)

December 2011

Guidance for industry: S6 Addendum to preclinical safety evaluation of biotechnology-derived

pharmaceuticals

May 2012

Guidance for industry: Preclinical assessment of investigational cellular and gene therapy

products

November 2013

Guidance for industry: Considerations for the design of early-phase clinical trials of cellular and

gene therapy products

June 2015

Guidance for industry: Source animal, Product, preclinical, and clinical issues concerning the use

of xenotransplantation products in humans

December 2016

Guidance for industry: Expedited programs for regenerative medicine therapies for serious

conditions

February 2019

Guidance for industry: Evaluation of devices used with regenerative medicine advanced

therapies

February 2019

Guidance for industry: Chemistry, manufacturing, and control (CMC) information for human

gene therapy investigational new drug applications (INDs)

January 2020

Guidance for industry: Studying multiple versions of a cellular or gene therapy product in an

early-phase clinical trial

November 2022

Draft guidance for industry: Potency assurance for cellular and gene therapy products December 2023

Guidance for industry: Considerations for the development of Chimeric antigen receptor (CAR)

T cell products.

January 2024

Guidance for industry: Human gene therapy products incorporating human genome editing January 2024

12. Considerations in the development of pluripotent stem cellebased therapies404

III. Specialty biologics and indications

This nascent ﬁeld is rapidly progressing, and new discoveries may impact regulatory

requirements and guidances. Early discussions with the FDA well in advance of the Pre-

Investigational New Drug (Pre-IND) meeting are therefore strongly encouraged for the devel-

opment of PSC-based therapeutic products. In the US, the FDA provides a format for these

early interactions through INTERACT meetings; an INitial Targeted Engagement for

Other regulatory guidances and resources for development of cellular therapies

Q5D quality of Biotechnological/Biological products: Derivation and characterization of cell

substrates used for production of Biotechnological/Biological products; availability

March 1998

PHS guideline on infectious disease issues in xenotransplantation January 2001

FDA guidance: Estimating the safe starting dose in clinical trials for therapeutics in adult healthy

volunteers

July 2005

ICH S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT

interval prolongation) by human pharmaceuticalsdscientiﬁc guideline

May 2005

US National Academies’ guidelines for human embryonic stem cell research; with Amendments 2005

2007, 2008

Guidance for industry: CGMP for phase 1 investigational drugs July 2008

National Institutes of health guidelines for human stem cell Research (https://stemcells.nih.gov/

research-policy/guidelines-for-human-stem-cell-research)

2009

Guidance for industry: Animal ModelseEssential elements to address efﬁcacy under animal rule February 2009

Final report of the National Academies’ human embryonic stem cell research Advisory

Committee and 2010 Amendments to the National Academies’ guidelines for human embryonic

stem cell research

2010

CFR 1271.75, 1271.80 and 1271.85 for donor screening and testing April 2010

Guidance for industry: ICH S6 [R1] nonclinical safety evaluation of biotechnology-derived

pharmaceuticals’

July 2011

EMEA guideline: Guideline on strategies to identify and Mitigate risks for ﬁrst-in-human and

early clinical trials with investigational Medicinal Product [R1]

July 2017

Guidance for industry: Expedited programs for regenerative medicine therapies for serious

conditions

February 2019

Guidance for industry: Evaluation of devices used with regenerative medicine advance therapies February 2019

ICH S7A safety pharmacology studies for human pharmaceuticalsdscientiﬁc guideline January 2021

International Society for stem cell Research’s guidelines for the stem cell research and clinical

translation https://www.isscr.org/guidelines

2021

International Society for stem cell Research’s standards for human stem cell use in research.

https://www.isscr.org/standards-document

2023

NIH stem cell Registry https://grants.nih.gov/stem_cells/registry/current.htm

Introduction 405

III. Specialty biologics and indications

<<< < Предыдущая 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 4142 / 4942 43 44 45 46 47 48 49 > Следующая >>>

Соседние файлы в папке Библиотека им академика М.И. Перельмана

#
12.10.20266 Мб0Книга_57_библиотеки_им_акад_М_И_Перельмана.pdf
#
30.08.202678 Мб0Книга_570_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_5700_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_5701_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20267 Мб0Книга_5702_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5703_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5704_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5705_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5706_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5707_Библиотеки_им_академика_М_И_Перельмана.pdf
#
12.10.20266 Мб0Книга_5708_Библиотеки_им_академика_М_И_Перельмана.pdf