Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5703_Библиотеки_им_академика_М_И_Перельмана
.pdf
Since the risk for autoimmunity was appreciated alongside the strong potential benefitof
the combined inhibition of LAG-3 and PD-1, the IND-enabling toxicology program for relat-
limab was designed to understand potential additive/synergistic adverse effects of the com-
bination therapy. In a 4-week repeat-dose toxicity study, cynomolgus monkeys were dosed
intravenously with five weekly doses of relatlimab at 30 or 100 mg/kg, nivolumab at
50 mg/kg, or a combination of relatlimab and nivolumab at 100 and 50 mg/kg, respectively,
followed by a 6-week recovery period ( Thudium et al., 2022). Both monotherapies were well
tolerated by monkeys with no adverse findings up to the highest administered doses, and a
NOAEL for relatlimab monotherapy was considered to be 100 mg/kg (NOAEL). However,
combination treatment of relatlimab and nivolumab was associated with higher incidence
and severity of inflammation in the central nervous system (choroid plexus, vasculature of
the brain paranchyma, meninges and spinal cord) as well as male reproductive tract (epidid-
ymis, seminal vesicles and testes), and resulted in the moribundity of one male monkey. The
histopathologic findings in the combination group were considered likely a result of
enhanced immunostimulatory effects resulting in loss of tolerance to self-antigens upon pro-
longed inhibition of both LAG-3 and PD-1 (Thudium et al., 2022; EMA Assessment Report:
Opdualag).
Pharmacodynamic endpoints in the 4-week repeat-dose toxicity study included an assess-
ment of TDAR (IgM, IgG and IgA) and ex vivo recall responses to intramuscularly adminis-
tered KLH, and immunophenotyping analyses of peripheral blood and splenic T-lymphocyte
subsets. The most prominent and noteworthy PD responses were noted in ex vivo T cell recall
assays upon restimulation with KLH, which indicated increased antigen -specific cytokine re-
sponses (CD69
þ
TNFa
þ
,CD69
þ
IFNg
þ
, CD69
þ
TNFa
þ
IFNg
þ
) in splenic CD4
þ
T cells in all
treated groups with a trend toward higher responses in the combination therapy group as
compared with monotherapy groups. These observed changes in ex vivo recall responses
tended to wane with declining exposures during the recovery phase (Thudium et al.,
2022). There were no changes in TDAR to KLH and no substantial changes in total T, B or
NK cell numbers in immunophenotyping. Minor changes in T cells subsets (e.g., CD4
þ
reg-
ulatory and CD25
þ
FoxP3
þ
CD8
þ
T cells) in the monotherapy and/or combination therapy
groups were considered related to high expression of the targets (i.e., LAG-3 and PD-1) on
regulatory T cells (EMA Assessment Report: Opdualag).
To support longer-term dos ing in the clinic and filing, a 3-month repeat-dose toxicity study
was conducted in sexually mature (4e7 year old) monkeys dosed intravenously with weekly
doses of relatlimab at 30 or 100 mg/kg followed by a 10-week recovery period (Thudium
et al., 2022 ). This study also included various assessments of PD (TDAR, immunophenotyp-
ing, and ex vivo recall responses). Consistent with the findings in the 4-week st udy, relatli-
mab was well tolerated with no adverse findings up to the highest administered dose level
of 100 mg/kg (NOAEL) (Thudium et al., 2022). In addition, there were no relatlimab-
related findings in reproductive organs (EMA Assessment Report: Opdualag).
No stand-alone safety pharmacology studies were conducted with relatlimab alone or in
combination with nivolumab. Safety pharmacology assessments, including clinical evalua-
tions of cardiovascular, respiratory, and neurologic fun ction, were included in repeat-dose
general toxicology studies. There were no effects on safety pharmacology parameters when
relatlimab was administered as a single agent or in combination with nivolumab in either
the 4-week or the 3-month repeat-dose toxicity studies (EMA Assessment Report: Opdualag).
11. Biological therapies for cancer386
III. Specialty biologics and indications
Since both LAG-3 and PD-1 are expressed on the surface of immune cells, an in vitro cyto-
kine release assay was conducted with relatlimab alone and in combination with nivolumab
in human PBMCs. Relatlimab, tested across a wide range of concentrations, did not induce
cytokine release in human PBMCs either alone or in combination with nivolumab (EMA
Assessment Report: Opdualag).
A tissue cross-reactivity study was conducted with labeled relatlimab to confirm LAG-3
expression in immune cells and assess any unexpected tissue binding using a select panel
of normal human tissues by IHC. Relatlimab showed strong positive staining in lymphocytes
as expected and consistent with previ ously published observations (Workman et al., 2002).
Unexpectedly, rare to occasional moderate/strong immunoreactivity was demonstrated
only in the adenohypophysis of the pituitary, which was further confirmed to be localized
to pituitary gonadotroph cells. Function of LAG-3 in the pituitary is unknown, but there
were no reported findings within the toxicity studies in monkeys suggestive of any adverse
effects on the pituitary or hypophyseal-portal system.
No carcinogenicity, genotoxicity or DART studies were conducted with relatlimab
(Opdualag Product Insert; EMA Assessment Report: Opdualag). The potential for LAG-3 in-
hibition to result in embryo-fetal effects was investigated using two murine surrogate anti-
LAG-3 antibodies in syngeneic and allogeneic mouse pregnancy models (Thompson et al.,
2019). The allogen eic mouse pregnancy model has been described as an alternative, relevant
model for assessing pharmacology-mediated reproductive liabilities of cancer immuno-
therapy mo lecules (Prell et al., 2016). However, treatment with murine anti-LAG -3 antibodies
did not result in any maternal or embryo-fetal development effects in either syngeneic or allo-
geneic crosses. Regardless, since Opdualag is a combination immunotherapy containing both
relatlimab and nivolumab, DART findings with nivolumab alone are applicable for the com-
bination. In a cynomolgus monkey ePPND study, administration of nivolumab from the
onset of organogenesis through delivery was associated with non-dose-related increase in
abortion and premature infant death, particularly in the third trimester (FDA Pharmacology
Review: Nivolumab; Opdualag Product Insert). Moreover, the function of the PD-1/PD-L1
axis in the maintenance of maternal-fetal immune tolerance (see PD-1 blockade and DART,
above) is well established (Zhang et al., 2015; Zeng et al., 2020; Guleria et al., 2005; Li et
al., 2021b). Therefore, the Opdualag labe l carries a warning that it may cause fetal harm
when administered to pregnant women, and women of reproductive potential are advised
to use effective contraception during treatment and for at least 5 months after the last admin-
istered dose (Opdualag Product Insert).
Recombinant analogs of endogenous human proteins (interferons, cytokines,
enzymes)
Interferons (IFN s) are types of cytokines that occur naturally in the body. While there are
three major types of IFNs: IFN alpha, IFN beta, and IFN gamma, IFN alpha is the type most
widely used in cancer treatment (Boyle, 2010). Researchers have found that IFNs can
improve the way a cancer p atient’ s immune system acts against cancer cells. In addition,
IFNs may act directly on cancer cells by slowing their growth or promoting their develop-
ment into cells with more normal behavior (Aguilar Rebolledo, 2000). IFNs may also
Recombinant analogs of endogenous human proteins (interferons, cytokines, enzymes) 387
III. Specialty biologics and indications
stimulate NK cells, T cells, and macrophages, boosting the immune system’santicancer
function. One issue with IFNs and other types of recombinant proteins is that ADAs that
develop to the recombinant product can cross-react to the respective endogenous proteins
and cause irreversible problems down the road such as chronic depletion of the endogenous
proteins and potential autoimmune phenomena, as the ADAs will persist in circulation long
after drug therap y has been ceased. This needs to be carefully monitored clinically and
cannot be predicted by animal species since human proteins are foreign to animals and
thus, depending on the species, animals are likely to develop some kind of ADA response
to human proteins.
Roferon-A
Roferon-A is a recombinant form of human IFN alpha for the treatment of certain types of
cancer, including hairy cell leukemia, melanoma, chro nic myeloid leukemia, and AIDS-
related Kaposi’s sarcoma (Trown et al., 1986). Studies have shown that IFN alpha may
also be effective in treating other cancers such as kidney cancer and non-Hodgkin’s lym-
phoma. The mechanism by which Roferon-A or any other IFN exerts antitumor or antiviral
activity is not clearly understood. However, it is believed that direct antiproliferative action
against tumor cells, inhibition of virus replication and modulation of the host immune
response play important roles in antitumor and antiviral activity (Roferon-A Prescribing In-
formation, 2024).
The biologic activity of IFNs that led to their discovery was their ability to protect cells
from infection with a variety of RNA and DNA viruses (Soetens, 2004; Isaacs, 1957). The anti-
viral activity of Roferon-A was compared in vitro with that of leukocyte IFN against a num-
ber of viruses. It was demonstrated that the relative antiviral activity of IFN alfa-2a was not
appreciably different from that of natural leukocyte IFN (i.e., it is representative of the
mixture of subtypes produced by leukocytes) (Kramer et al., 1983). The antiviral activity of
Roferon-A was then compared with that of leukocyte IFN in cell lines from a num ber of an-
imal species and was shown to be considerably species-restricted. Roferon-A was active in
human cells as well as cells from bovines, African green monkeys, and guinea pigs, but inac-
tive in cells from mice, hamsters, and rabbits (Soetens, 2004; Weck et al., 1981; Stebbing et al.,
1983; Soike, 1983; Kern et al., 1983). As a consequence, preclinical evaluation of Roferon-A has
involved in vitro experiments with human cells and in vivo studies in nude mice and rhesus
monkeys. Because of its species-restricted activity, it has not been possible to demonstrate
antitumor activity in immunologically intact syngeneic tumor model systems, where effects
on the host immune system would be observable. However, such antitumor activity has
been demonstrated with mouse interferon alfa in transplantab le mouse tumor systems. The
clinical significance of these findings is unknown. Roferon-A has been shown to inhibit the
growth of several human tumors growing in immunocompromised (nude) mice (Soetens,
2004).
The development of Roferon-A as a medicine commenced in the early days of biotech-
nology product development in the late 1970s and early 1980s. The toxicologic evaluation
of interferon alfa-2a presented unique problems not seen with typical small-molecule drugs.
One early problem was that despite the use of recombinant DNA techniques, highly purified
IFN alfa-2a was in short supply. It was not possible to design studies at high multiples over
11. Biological therapies for cancer388
III. Specialty biologics and indications
the expected human dose. At the time, clinical trials with Roferon-A began, however, there
was already considerable clinical experience with leukocyte interferon to inform on the na-
ture of the adverse effects that might be expected (Soetens, 2004).
Therefore, to support clinical dosing, single-dose studies were conducted in mice, rats, rab-
bits, and ferrets at doses up to 500 10
6
units/kg using various routes of administration (IV,
IM, and SC) and local tolerance was assessed in mice (IV), rats (IV), and rabbits (IM) (Mertes
and Laxenaire, 2002). The purpose of these studies was to confirm that there was no unex-
pected acute toxicity when clinical dosage forms were given to a variety of animals by
various routes. Therefore, these assessments were as much safety evaluations of the excipi-
ents contained in the clinical formulation as they were safety studies of Roferon-A itself, espe-
cially given that mice and rabbits are not relevant species based on in vitro cell-activation
data. The animals were given single doses and observed for 14 days. No mortality, local intol-
erance, or clinical signs related to treatment with Roferon-A were observed in these studies.
Subchronic toxicity studies with Roferon-A were conducted in mice (2 weeks), squirrel mon-
keys (4 weeks), rhesus monkeys (5 weeks), and cynomolgus monkeys (13 weeks) (Soetens,
2004). In mice, except for reversible, dose-related increases in platelet and certain leukocyte
count parameters, no effects related to Roferon-A treatment were observed. The squirrel
monkey was chosen because Roferon-A had been reported to have antiviral efficacy in that
species. Only one dose level of 2.5 10
6
units/kg per day was used because of limited sup-
ply, and only slight decreases in hemoglobin and hematocrit levels were observed. Roferon-A
was tested at doses up to 25 10
6
units/kg per day in DART dose range finding studies us-
ing rhesus monkeys (Soetens, 2004). The only treatment-related finding was dose-d ependent
anorexia, with associated weight loss. In the cynomolgus monkey study, there were no
treatment-related adverse findings at doses up to 10 10
6
units/kg per day except for tran-
sient anorexia, which occurred during the first 5 weeks and then disappeared with continued
treatment. Antibodies to Roferon-A developed in all studies and further complicated the
interpretation of these toxicology studies. In summary, these toxicology studies were not
considered very predictive due to the very low frequency of treatment-related adverse find-
ings, in contrast with the high frequency of side-effects subsequently observed in clinical tri-
als. As noted ab ove, this may have been a result of species-restricted activity and/or high
frequency of ADAs. Toxicology studies might be more predictive if homologous alpha-
interferons had been used in each species studied (Soetens, 2004).
Data in the literature concerning the genotoxicity of human leukocyte interferon are mixed
[94]. A chromosomal defect was observed following the addition of human leukocyte inter-
feron to lymphocyte cultures from a patient suffering from a lymphoproliferative disorder. In
contrast, other studies have failed to detect chromosomal abnormalities following treatment
of lymphocyte cultures from healthy volunteers with human leukocyte interferon. It has also
been shown that human leukocyte interferon actually protects primary chick embryo fibro-
blasts from chromosomal aberrations produced by gamma rays. However, no evidence of
mutagenicity was observed in Ames tests using six different tester strains, with and without
metabolic activation, up to a concentration of 1920 mg/plate. Furthermore, no increase in the
incidence of chromosomal damage was noted when human lymphocyte cultures were
treated in vitro with Roferon-A at noncytotoxic concentrations. Roferon-A was not been
tested for its carcinogenic potential, consistent with ICH guidance ( Mertes and Laxenaire,
2002; Yoshizawa et al., 2005).
Recombinant analogs of endogenous human proteins (interferons, cytokines, enzymes) 389
III. Specialty biologics and indications
Since Roferon-A was intended for use in women of childbearing potential without life-
threatening disease, reproductive toxicology studies were carried out in the rhesus monkey
(Soetens, 2004; Mertes and Laxenaire, 2002). Nonpregnant female monkeys were given daily
IM doses of 1, 5, or 25 10
6
units/kg for three consecutive men strual cycles. At the higher
doses of five and 25 10
6
units/kg per day, the menstrual cycles and cyclic serum hormone
levels were disrupted, which manifested as prolonged or shortened menstrual periods and
erratic bleeding; these cycles were considered to be anovulatory on the basis that reduced
progesterone levels were noted and that expected increases in preovulatory estrogen and
luteinizing hormones were not observed. These monkeys returned to a normal menstrual
rhythm following discontinuation of treatment. When pregnant female rhesus monkeys
were treated with the same doses of Roferon-A (approximately 20e 500 times the human
weekly dose, when scaled by body surface area) during the early to midfetal period of organ-
ogenesis from weeks 3e10 of gestation, a dose-dependent increase in the incidence of abor-
tions occurred. Abortifacient activity was also observed in two out of six pregnant rhesus
monkeys treated with 25 10
6
units/kg per day Roferon-A (500 times the human dose) dur-
ing the period of late fetal development (days 79e100 of gestation). No teratogenic effects
were seen in either study (Mertes and Laxenaire, 2002). Since the validity of extrapolating
doses used in animal studies to human doses is not established for Roferon-A, it is to be
used during pregnancy only if the potential benefit to the woman justifies the potential
risk to the fetus and only when they are using effective contraception during therapy. In addi-
tion, the injectable solution contains benzyl alcohol, which can be transmitted via the
placenta. Therefore, if Roferon-A is administered during pregnancy, the possibility of toxicity
to the developing fetus should be carefully assessed (Mertes and Laxenaire, 2002).
Summary
Increased understanding of the biology of cancer has allowed for the identification of novel
molecular targets for drug development. The high selectivity and affinity for the intended
target and decreased toxicity compared with traditional chemotherapies has translated to bio-
logic drugs being poised as critical players in the treatment of various cancers. With an ever-
increasing number of biologics in development, there are now more hopes of achieving
greater antitumor efficacy by combining biologic therapeutics with chemotherapy, radio-
therapy, and/or other biologics. However, the high costs, prolonged timelines and lack of
predictive nonclinical models continue to pose challenges for the development of new
oncology drugs. Moreover, oncology therapeutics are also less likely to reach the market
than those in other clinical fields despite high levels of investment. Nonclinical testing stra-
tegies for biologics have to be adapted and refined from experience with small molecules,
and should contribute to reducing the high attrition rates in drug development by being as
predictive as possible of clinical efficacy. Well-designed nonclinical development plans
with innovative study designs shorten the time to the delivery of safer therapeutics, and
should be considered an integral step for success of new biologic drugs.
The develop ment of biologic drugs comes with its own share of challenges. Since the
toxicity of most biologics is related to the mechanism of action, a thorough understanding
of the pharmacological target(s) is the critical first step in their nonclinical development.
11. Biological therapies for cancer390
III. Specialty biologics and indications
Second, species appropriateness for nonclinical studies based on target expression, cross-
reactivity, pharmacokinetics, etc., should be given due consideration. In general, the nonclin-
ical development of oncology biologics entails standard toxicology studies in two species
(rodent and nonrodent). However, depending on cross-reactivity, the use of a single pharma-
cologically relevant NHP species can be justified. Studies in human cells and transgenic mice
and the use of homologs or surrogate equivalents in rodents may also be necessary, and can
contribute to the safety assessment of the clinical candidate. Additional specialty toxicology
assessments should be conducted in alignment with the ICH guidances if warranted based on
a specific concern relative to the pharmacology of the given biologic. Immunotoxicological
evaluations may especially be warranted since a considerable number of biologic therapeutics
in development for oncology indications are intended to stimulate or suppress the immune
system. In addition, since human biologics are inherently immunogenic in nonclinical test
species, a thorough assessment of the immunogenicity profile is vital for the establishment
of the drug’s safety profile, as well as PK and PD interpretations. Finally, specific assays to
measure PD responses may need to be designed and incorporated into nonclinical studies
as markers of both safety and in vivo efficacy.
As has been illustrated in the above secti ons, the nonclinical development of oncology bio-
logic therapeutics is custom tailored with a particular focus on pharmacologic (i.e., target-
mediated) toxicities. Well-designed nonclinical studies aid in clinical dose selection and
regimen, and contribute significantly to the clinical safety monitoring plan. The type, timing
and flexibility called for in designing nonclinical studies for oncology biologics often differ
from other types of pharmaceuticals. Therefore, the ICH S9, S6(R1), and M3 guidances should
be used in combination to craft a comprehensive nonclinical development plan on a case-
specific basis. While the aforementioned ICH guidances provide the overall requirements,
the approach to nonclinical study design, conduct and endpoints to be included must be
driven by scientific rationale. As has been emphasized throughout the chapter, consultation
with Health Authorities regarding the sufficiency of nonclinical data packages to support
FIH, late stage clinical, and marketing phase of development are strongly encouraged.
References
Aguilar Rebolledo F. Interferons in neurology. Rev Invest Clin 2000;52:665e79.
Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) as a cancer immunotherapy target. Immunol
Rev 2017;276(1):80e96.
Baumann A. Preclinical development of therapeutic biologics. Expert Opin Drug Discov 2008;8(3):289e97.
Baxevanis CN, Perez SA, Papamichail M. Combinatorial treatments including vaccines, chemotherapy and mono-
clonal antibodies for cancer therapy. Cancer Immunol Immunother 2009;58:317e24.
Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug
bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha
inhibitor infliximab. Arthritis Rheum 2006;54(12):3782e9.
Borgstrom P, Hillan KJ, Sriramarao P, Ferrara N. Complete inhibition of angiogenesis and growth of microtumors by
antivascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital
videomicroscopy. Cancer Res 1996;56(17):4032e9.
Borgstrom P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N. Neutralizing anti-vascular endothelial growth factor
antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Pros-
tate 1998;35(1):1e10.
Boyle RM. The use of biologics in cancer therapy. US Pharm 2010;35(3):4e7. Oncology suppl.
References 391
III. Specialty biologics and indications
Bria E, Cuppone F, Milella M, Verma S, Carlini P, Nistico C, et al. Trastuzumab cardiotoxicity: biological hypotheses
and clinical open issues. Expert Opin Biol Ther 2008;8:1963e71.
Brown PC, Wange RL. Considerations regarding the use of nonhuman primates in assessing safety endpoints for
pharmaceuticals. Reg Toxicol Pharmacol 2023;143:105449.
Bugelski PJ, Martin PL. Concordance of preclinical and clinical pharmacology and toxicology of therapeutic mono-
clonal antibodies and fusion proteins: cell surface targets. Br J Pharmacol 2012;166:823e46.
Bugelski PJ, Herzyk DJ, Rehm S, Harmsen AG, Gore EV, Williams DM, et al. Preclinical development of keliximab, a
primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and
safety studies. Hum Exp Toxicol 2000;19(4):230e43.
Bumbaca D, Wong A, Drake E, Reyes 2nd AE, Lin BC, Stephan JP, et al. Highly specific off-target binding identified
and eliminated during the humanization of an antibody against FGF receptor 4. mAbs 2011;3(4):376e86.
Bussiere J. Species selection considerations for preclinical toxicology studies for biotherapeutics. Expert Opin Drug
Metab Toxicol 2008;4(7):871e7.
Caravella J, Lugovskoy A. Design of next-generation protein therapeutics. Curr Opin Chem Biol 2010;14:520e8.
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development
and lethality in embryos lacking a single VEGF allele. Nature 1996;380(6573):435e9.
Carter P, Presta L, Gorman CM, Ridgway JBB, Henner D, Wong WLT, et al. Humanization of an anti-p185HER2 anti-
body for human cancer therapy. Proc Natl Acad Sci U S A 1992;89:4285e9.
Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4 deficient mice is mediated by costimulation-
dependent activation of CD4þ T cells. Immunity 1997;7(6):885e95.
Chen C, Constantinou A, Chester KA, Vyas B, Canis K, Haslam SM, et al. Glycoengineering approach to half-life
extension of recombinant biotherapeutics. Bioconjug Chem 2012;23(8):1524e33.
Chiriva-Internati M, Grizzi F, Wachtel MS, Jenkins M, Ferrari R, Cobos E, et al. Biological treatment for liver tumor
and new potential biomarkers. Dig Dis Sci 2008;53:836e43.
Chocorro L, Bocanegra A, Blanco E, Fernandez-Rubio L, Arasanz H, Echaide M, et al. Cutting-edge: preclinical and
clinical development of the first approved lag-3 inhibitor. Cells 2022;11:2351.
Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, et al. Vascular permeability factor: a tumor-derived
polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.
J Exp Med 1990;172(6):1535e45.
Coiffier B. Rituximab therapy in malignant lymphoma. Oncogene 2007;26:3603e13.
DeGeorge JJ, Ahn C-H, Andrews PA, Brower ME, Giorgio DW, Goheer MA, et al. Regulatory considerations for pre-
clinical development of anticancer drugs. Cancer Chemother Pharmacol 1998;41:173e85.
Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor,
microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146(5):1029e39.
Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy.
Nat Immunol 2002;3(7):611e8.
European Medicines Agency. Scientific discussion on Rituximab. 2005. http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Scientific_Discussion/human/000165/WC500025817.pdf2005.
European Medicines Agency. Assessment report for Ipilimumab. 2011. http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Public_assessment_report/human/002213/WC500109302.pdf2011.
Fanale MA, Uyei AR, Theriault RL, Adam K, Thompson RA. Treatment of metastatic breast cancer with trastuzumab
and vinorelbine during pregnancy. Clin Breast Cancer 2005;6(4):354e6.
Ferrara N, Gerber HP. The role of vascular endothelial growth factor in angiogenesis. Acta Haematol
2001;106(4):148e56.
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’
Shea KS, et al. Heterozygous embryonic lethality induced by
targeted inactivation of the VEGF gene. Nature 1996;380(6573):439e42.
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18(1):4e25.
Fleischmann RM. Safety of biologic therapy in rheumatoidarthritis and other autoimmune diseases: focus on ritux-
imab. Semin Arthritis Rheum 2009;38:265e80.
Floyd E, McShane TM. Development and use of biomarkers in oncology drug development. Toxicol Pathol
2004;32(1):106e15.
Fu J, Wang F, Dong L, Zhang J, Deng C, Wang X, et al. Preclinical evaluation of the efficacy, pharmacokinetics and
immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin
2017;38:710e8.
11. Biological therapies for cancer392
III. Specialty biologics and indications
Gaufin T, Pattison M, Gautam R, Stoulig C, Dufour J, MacFarland J, et al. Effect of B-cell depletion on viral replication
and clinical outcome of simian immunodeficiency virus infection in a natural host. J Virol 2009;83:10347e57.
Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, et al. Vascular endothelial growth factor regulates
endothelial cell survival through the phosphatidylinositol 3
0
-kinase/Akt signal transduction pathway. Require-
ment for Flk-1/KDR activation. J Biol Chem 1998;273(46):30336e43.
Goldenberg DM, Morschhauser F, Wegener WA. Veltuzumab (humanized anti-CD20 monoclonal antibody): charac-
terization, current clinical results, and future prospects. Leuk Lymphoma 2010;51:747e55.
Gregory SA, Hohloch K, Gisselbrecht C, Tobinai K, Dreyling M, et al. Harnessing the energy: development of radio-
immunotherapy for patients with non-Hodgkin’s lymphoma. Oncology 2009;14(Suppl. 2):4e16.
Grimaldi C, Finco D, Fort MM, Gliddon D, Harper K, Helms WS, et al. Cytokine release: a workshop proceedings on
the state-of-the-science, current challenges and future directions. Cytokine 2016;85:101e8.
Grimaldi C, Ibraghimov A, Kiessling A, Rattel B, Ji C, Fuller CL, et al. Current nonclinical approaches for immune
assessments of immuno-oncology biotherapeutics. Drug Discov Today 2023;28(2):103440.
Gros A, Robbins PF, Yao S, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8⁺ tumor-reactive
repertoire infiltrating human tumors. J Clin Invest 2014;124(5):2246e59.
Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, et al. A critical role for the programmed death
ligand 1 in fetomaternal tolerance. J Exp Med 2005;202(2):231e7.
Haller CA, Cosenza ME, Sullivan JT. Safety issues specific to clinical development of protein therapeutics. Clin Phar-
macol Therap 2008;84(5):624e7.
Hammond E, Haynes NM, Cullinane C, Brennan T, Bampton D, Handley P, et al. Immunomodulatory activities of
pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors.
J Immunother Cancer 2018;6:54.
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current research in cancer. Am J Cancer Res 2020;10(3):727e42.
Health Canada. Product monograph for Herceptin. 2004. http://rochecanada.com/fmfiles/re7234008/Research/
ClinicalTrialsForms/Products/ConsumerInformation/MonographsandPublicAdvisories/Herceptin/herceptin
Sept14SIE.pdf.
Hodgson DR, Whittaker RD, Herath A, Amakye D, Clack G. Biomarkers in oncology drug development. Mol Oncol
2009;3:24e32.
Hotz HG, Hines OJ, Hotz B, Foitzik T, Buhr HJ, Reber HA. Evaluation of vascular endothelial growth factor blockade
and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer.
J Gastrointest Surg 2003;7(2):220e7. discussion 227e8.
Howdieshell TR, Riegner C, Gupta V, Callaway D, Grembowicz K, Sathyanarayana, et al. Normoxic wound fluid
contains high levels of vascular endothelial growth factor. Ann Surg 1998;228(5):707e15.
Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB. Vascular endothelial growth factor immunoneutral-
ization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer.
Am J Pathol 2002;161(5):1917e24.
Hutchins B, Starling GC, McCoy MA, Herzyk D, Poulet FM, Dulos J, et al. Biophysical and immunological charac-
terization and in vivo pharmacokinetics and toxicology in nonhuman primates of the anti-PD-1 antibody pembro-
lizumab. Mol Cancer Ther 2020;19(6):1298e307.
ICH Topic S1a. Guideline on the need for carcinogenicity studies of pharmaceuticals. Current Step 4 version Dated
Nov 1995.
ICH Topic M3 (R2). Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing
authorization for pharmaceuticals. Current Step 4 version Dated June 2009.
ICH Topic S6. Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Current Step 4 version Dated
July 1997 (Addendum incorporated 2011).
ICH Topic S9. Nonclinical evaluation for anticancer pharmaceuticals. Current Step 4 version Dated March 2010.
ICH Topic S9 Questions and answers:nonclinical evaluation for anticancer pharmaceuticals. Step 5 April 2018.
Isaacs A, Lindenmann J. Virus interference: I. The interferon. Proc R Soc Lond [B] 1957;147:258e67.
Kamperschroer C, Shenton J, Lebrec H, Leighton JK, Moore PA, Thomas O. Summary of a workshop on preclinical
and translational safety assessment of CD3 bispecifics. J Immunotoxicol 2020;17(1):67e85.
References 393
III. Specialty biologics and indications
Kern ER, Richards JT, Overall JJC, Kramer MJ, Trown PW. Effective treatment of a genital herpes simplex virus type 2
infection ofguinea pigs with recombinant human leukocyte A interferon. Proc 13th Int Cong Chemother
1983;6:60/31e60/34.
Kim ES, Soffer SZ, Huang J, McCrudden KW, Yokoi A, Manley CA, et al. Distinct response of experimental neuro-
blastoma to combination antiangiogenic strategies. J Pediatr Surg 2002;37(3):518e22.
Kim KJ, Li B, Houck K, Winer J, Ferrara N. The vascular endothelial growth factor proteins: identification of biolog-
ically relevant regions by neutralizing monoclonal antibodies. Growth Factors 1992;7(1):53e64.
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-
induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362(6423):841e4.
Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456e73.
Kramer MJ, Dennin R, Kramer C, Jones G, Connell E, Rolon N, et al. Cell and virus sensitivity studies with recom-
binant human alpha interferons. J Interferon Res 1983;41:1e416.
Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth factor induces EDRF-dependent relaxation in cor-
onary arteries. Am J Physiol 1993;265(2 Pt 2):H586e92.
Kummar S, Gutierrez M, Doroshow JH, Murgo AJ. Drug development in oncology: classical cytotoxics and molec-
ularly targeted agents. Br J Clin Pharmacol 2006;62(1):15e26.
Kumar S, Ghosh S, Sharma G, Wang Z, Kehry MR, Marino MH, et al. Preclinical characterization of dostarlimab, a
therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and
in vivo animal models. mAbs 2021;13:1.
Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, et al. Anti-vascular endothelial growth
factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res
2000;60(19):5565e70.
Lee KS. Requirement for neuroregulin receptor, erbB2, in neural and cardiac development. Nature 1995;379:394e6.
Li T, Chen Y, Lai Y, He G, He G, He G. Expression and significance of PD-1 and PD-L1 in patients with recurrent
spontaneous abortion. Medicine 2021a;100(14):e25444.
Li WX, Xu XH, Jin LP. Regulation of the innate immune cells during pregnancy: an immune checkpoint perspective.
J Cell Mol Med 2021b;25(22):10362e75.
MacLachlan TK, Price S, Cavagnaro J, Andrews L, Blanset D, Cosenza ME, et al. Classic and evolving approaches to
evaluating cross reactivity of mAb and mAb-like molecules e a survey of industry 2008e2019. Regul Toxicol
Pharmacol 2021;121.
Maitland ML, Schilsky RL. Clinical trials in the era of personalized oncology. Cancer J Clin 2011;61(6):365e81.
Mayer L, Young Y. Infusion reactions and their management. Gastroenterol Clin N Am 2006;35:857e66.
McCrudden KW, Hopkins B, Frischer J, Novikov A, Huang J, Kadenhe A, et al. Anti-VEGF antibody in experimental
hepatoblastoma: suppression of tumor growth and altered angiogenesis. J Pediatr Surg 2003;38(3):308e14.
Mertes PM, Laxenaire MC. Allergic reactions occurring during anaesthesia. Eur J Anaesthesiol 2002;19(4):240e62.
Mesiano S, Ferrara N, Jaffe RB. Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites for-
mation by immunoneutralization. Am J Pathol 1998;153(4):1249e56.
Misbah SA, Chapel HE. Adverse effects of intravenous immunoglobulin. Drug Saf 1993;9(4):254e62.
Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA. Vascular endothelial growth factor mediates
angiogenic activity during the proliferative phase of wound healing. Am J Pathol 1998;152(6):1445e52.
Ochsner AJ. Cardiovascular and respiratory responses to ketamine hydrochloride in the rhesus monkey (Macaca
mulatta). Lab Anim Sci 1977;27(1):69e71.
O’Conner A. Introduction to biotech drugs. Reg Rapport 2009;6(1):4e7.
Poulet FM, Wolf JJ, Herzyk DJ, DeGeorge JJ. An evaluation of the impact of PD-1 pathway blockade on reproductive
safety of therapeutic PD-1 inhibitors. Birth Defects Res B Dev Reprod Toxicol 2016;107(2):108e19.
Prell RA, Halpern WG, Rao GK. Perspective on a modified developmental and reproductive toxicity testing strategy
for cancer immunotherapy. Int J Toxicol 2016;35(3):263e73.
Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endo-
thelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res
1997;57(20):4593e9.
Prueksaritanont T, Tang C. ADME of biologicsdwhat have we learned from small molecules? AAPS J
2012;14(3):410e9.
Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapydrare but
there! Leuk Lymphoma 2009;50:1083e95.
11. Biological therapies for cancer394
III. Specialty biologics and indications
Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric
mousehuman monoclonal antibody to CD20. Blood 1994;83:435e45.
Rituxan USPI. 2014 www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf2011.
Roferon-A, 2024 Roferon-A prescribing information (Roferon-A Label). http://dailymed.nlm.nih.gov/dailymed/
drugInfo.cfm?id¼8326.
Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, et al. Preclinical safety evaluation of rhuMAb-
VEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 1999;27(1):78e86.
Schuster M, Nechansky A, Kircheis R. Cancer immunotherapy. Biotechnol J 2006;1:138e47.
Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA
Cancer J Clin 2006;56:226e43.
Shima DT, Gougos A, Miller JW, Tolentino M, Robinson G, Adamis AP, et al. Cloning and mRNA expression of
vascular endothelial growth factor in ischemic retinas of Macaca fascicularis. Invest Ophthalmol Vis Sci
1996;37(7):1334e40.
Skaggs H, Chellman GJ, Collinge M, Enright B, Fuller CL, Krayer J, et al. Comparison of immune system develop-
ment in nonclinical species and humans: closing information gaps for immunotoxicity testing and human trans-
latability. Reprod Toxicol 2019;89:178e88.
Soetens FM. Anaphylaxis during anaesthesia:diagnosis and treatment. Acta Anaesthesiol Belg 2004;55(4):229e37.
Soffer SZ, Moore JT, Kim E, Huang J, Yokoi A, Manley C, et al. Combination antiangiogenic therapy: increased ef-
ficacy in a murine model of Wilms tumor. J Pediatr Surg 2001;36(8):1177e81.
Soike KF, Kramer MJ, Gerone PJ. In vivo antiviral activity of recombinant type a interferon A in monkeys with infec-
tions due to simian varicella virus. J Infect Dis 1983;147:933e8.
Stebbing N, Weck PK, Fenno JT, Estell DA, Rinderknecht E. Antiviral effects of bacteria-derived human leukocyte
interferon against encephalomyocarditisvirus infection of squirrel monkeys. Arch Virol 1983;76(4):365e7.
Stubenrauch K, Wessels U, Essig U, Vogel R, Schleypen J. Evaluation of a generic immunoassay with drug tolerance
to detect immune complexes in serum samples from cynomolgus monkeys after administration of human anti-
bodies. J Pharm Biomed Anal 2010;52(2):249e54.
Sweeney CJ, Miller KD, Sissons SE, Nozaki S, Heilman DK, Shen J, et al. The antiangiogenic property of docetaxel is
synergistic with are combinant humanized monoclonal antibody against vascular endothelial growth factor or 2-
methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 2001;61(8):3369e72.
Tabrizi MA, Roskos LK. Preclinical and clinical safety of monoclonal antibodies. Drug Disc Today
2007;12(13e14):540e7.
Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Gutiérrez EC, et al. Relatlimab and nivolumab
versus nivolumab in untreated advanced melanoma. N Engl J Med 2022;386:24e34.
Thompson KE, Danberry TL, Bunch RT, Graziano MJ, McNerney ME. Allogeneic murine pregnancy models for
assessing the developmental effects of immune-stimulating antibodies: challenges in reproducibility. Birth Defects
Res 2019:1e14.
Thudium K, Selby M, Zorn JA, Rak G, Wang X-T, Bunch RT, et al. Preclinical characterization of relatlimab, a human
LAG-3eblocking antibody, alone or in combination with nivolumab. Cancer Immunol Res 2022;10(10):1175e89.
Tibbitts J, Cavagnaro JA, Haller CA, Marafino B, Andrews PA, Sullivan JT. Practical approaches to dose selection for
first-in-human clinical trials with novel biopharmaceuticals. Reg Toxicol Pharmacol 2010;58:243e51.
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH, et al. Loss of CTLA-4 leads to massive
lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-
4. Immunity 1995;3(5):541e7.
Tonnesen MG, Feng X, Clark RA. Angiogenesis in wound healing. J Invest Dermatol Symp Proc 2000;5(1):40e6.
Trown PW, Wills RJ, Kamm JJ. The preclinical development of Roferon-A. Cancer 1986;57:1648
e56.
U.S. Food and Drug Administration. Nonclinical considerations for mitigating nonhuman primate supply constraints
arising from the COVID-19 pandemic. FDA; Feb 2022.
Vaidyanathan A, McKeever K, Anand B, Eppler S, Weinbauer GF, Beyer JC. Developmental immunotoxicology
assessment ofrituximab in cynomolgus monkeys. Toxicol Sci 2011;119:116e25.
Vessillier S, Fort M, O’Donnell L, Hinton H, Nadwodny K, Piccotti J, et al., Participants of the study. Development of
the first reference antibody panel for qualification and validation of cytokine release assay platforms e report of
an international collaborative study. Cytokine X 2020;2(4):100042.
Wang T, Jacobson-Kram D, Pilaro AM, Lapadula D, Jacobs A, Brown P, et al. ICH Guidances: inception, revision, and
implementation for drug development. Toxicol Sci 2010;118(2):356e7.
References 395
III. Specialty biologics and indications
Соседние файлы в папке Библиотека им академика М.И. Перельмана