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toxicity, a longer half-life may also prolong undesirable side effects. For small molecule com-
pounds, a delicate balance exists between PK exposure (maximum serum/plasma concentra-
tion (C
max
), area-under-the concentration time curve (AUC), minimum threshold
concentration) needed to elicit the intended pharmacological effect and exposures that are
too low (not ef ficacious) or too high (toxic). The following sections discuss some of the differ-
ences between biologics and small molecules highlighted above in greater detail.
Routes of administration
A key distinction between biologics and small molecules is in the route of administration.
Unlike systemically available small molecule drugs that are often formulated to enable oral
delivery, biologics historically have not been administere d orally due to their poor transport
across the intestinal membrane, poor absorption into systemic circulation (Anselmo et al.,
2019), and their sensitivity to enzymatic catabolism in the gastrointestinal tract. The majority
of biologics are therefore delivered parenterally (IV, subcutaneously [SC], or, in the case of
many vaccines, intramuscularly [IM]). IV administration is advantageous because it affords
100% bioavailability and rapid distribution to all vascularized tissues, as well as higher injec-
tion volumes relative to other parenteral routes. The most notable disadvantage of IV admin-
istration is that it lacks convenience because patients cannot administer doses at home.
Additionally, the near-immediate systemic availability of IV administered drugs may limit
the dose that can be given due to toxicity.
The SC dose route shortens the infusion time, relative to IV administration, and enables
self-administration, factors that are likely to increase patient compliance; additionally, the
slow release of a biologic from the site of SC administration prolongs its half-life and de-
creases the frequency of administration required. Further, SC dosing may mitigate toxicity
because the C
max
is blunted relative to IV administration. A limitation of the SC route is
the injection volume that can be administered without pain (a maximum of 2e2.5 mL) and
formulation issues that may arise that limit the delivered amount of the therapeutic in an
SC dose. Strategies to overcome volume limitations include the development of high concen-
tration formulations and coformulation with recombinant human hyaluronidase (rHuPH20),
which transiently depolymerizes hyaluronan in the extracellular matrix of the subcutaneous
space to facilitate the dispersion and absorption of SC-administered drugs. Several biologics
coformulated with rHuPH20 have received regulatory approval, including HYQVIA
(immune globulin infusion), Herceptin HYLECTA (trastuzumab; marketed as Herceptin SC
in Europe), DARZALEX FASPRO (daratumumab), RITUXAN HYCELA (rituximab; mar-
keted as MabThera SC in Europe), and PHESGO (pertuzumab and trastuzumab) (Knowles
et al., 2021). An alternative strategy to enable SC administration of biologics is formulation
using polymeric encapsulation. For example, a recent study evaluating the biophysical char-
acteristics of proteins, inc luding IgG antibodies, incubat ed with concentrated solutions of
poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-
PEG-PLGA triblock copolymer) and injected SC in rats and minipigs demonstrated that
the released proteins were active and conformationally stable and that protein release lasted
for up to 35 days (Dutta et al., 2020). A number of polymer-based peptide depot produ cts
have achieved clinical and commercial success, including BYDUREON BCise (exenatide), Eli-
gard (leuprolide), and Nutropin Depot (somatropin; discontinued in 2004).
1. Overview of biopharmaceuticals and comparison with small-molecule drug development6
I. Development of biopharmaceuticals
Despite the challenges of oral delivery of biologics, this is an active area of study to
improve patient convenience and compliance relative to parenteral dose administration.
The first oral glucagon-like peptide 1 (GLP-1) receptor agonist product, Rybelsus, was
approved by the US FDA in 2019. Numerous approaches such as nanoparticles, hydrogels,
permeation enhancers, and mucoadhesive modifications (Anselmo et al., 2019; Cao et al.,
2021), and highly innovative technologies as a robotic pill (Dhalla et al., 2022) and a gastric
autoinjector (Abramson et al., 2022) are also being evaluated.
Additional alternate routes of administration intended to increase patient convenience and
compliance and, in some cases, to deliver biotherap eutics at their site of action, include pul-
monary/inhalation, transdermal, nasal and buccal, intratumoral, intrathecal, and intravesic-
ular. Extensive nonclinical efforts and clinical trials are ongoing to optimize delivery
characteristics and evaluate the efficacy and safety of molecules administered by these routes
(Anselmo et al., 2019).
Nonclinical species for toxicology testing
Another key distinction between small molecules and biologics is in the species utilized for
nonclinical safety evaluation. Regulatory guidances (e.g., ICH M3 (ICH, 2009)) specify that,
for small molecules, the nonclinical safety profile should be evaluated in two mammalian
species (i.e., one rodent and one nonrodent), whereas for biotherapeutics, due to their highly
targeted nature, emphasis is placed on the selection of pharmacologically relevant species for
nonclinical safety evaluation. The species relevance for small molecules is primarily focused
on comparable systemic exposures and in vitro/in vivo metab olite profiling. In addition, it is
beneficial to select a species that has known pharmacologic relevance to address any target-
based risks in addition to off-target effects often observed with small molecules. Importantly,
toxicity studies in two species increases the probability that any clinical risks are identified in
at least one of the species and hence provides more thorough hazard identification prior to
the initiation of clinical trials.
While studies of biologics should be conducted in two species if they are both relevant,
regulatory authorities accept the submission of toxicology studies in a single species due to
limited species relevance. The assessment of relevance depends on several factors, including
the expression and functional activity of the target(s) in the nonclinical species to con firm
comparability of the expression pattern of the target between species and ensure the pharma-
cologic activity of the biologic in the nonclinical species. The nature of binding of the biologic
to the target (i.e., binding affinity) should also be comparable between humans and the
nonclinical species; if the binding affinity in nonclinical species is much lower than in human,
this may necessitate alterations to toxicology study design (e.g., increased dose level, correc-
tion factors to achieve human equivalent dose and/or exposure margins) or it may preclude
the conduct of nonclinical toxicology studies altogether.
Consistent with the principles of the 3Rs of ethical animal use (reduce/refine/replace; Rus-
sell and Burch, 1959), the most recent update of ICH S6 (ICH S6(R1), 2011) specifies that for
biotherapeutics with broad cross-reactivity in both rodent and nonrodent species, longer term
studies may be performed in rodents provided there are no substantive differences in the ef-
fects observed between species in shorter duration studies.
Nonclinical species for toxicology testing 7
I. Development of biopharmaceuticals
An issue largely specific to biotherapeutics is the potential for the development of immu-
nogenicity in nonclinical species. Because biotherapeutics are human or humanized proteins,
they may be recognized as foreign by the immune system of nonclinical species and an antith-
erapeutic (antidrug) antibody response may develop. While it is possible that these anti-
bodies may have no consequences, the potential concerns related to their development
include alterat ions in exposure (increase or decrease) due to antitherap eutic antibody binding
to the biotherapeutic and/or the development of adverse effects related to the formation of
antibody complexes (Bussiere, 2008; Kronenberg et al., 2017; Rojko et al., 2014). The timing
of the development of antitherapeutic antibodies may preclude the completion of long dura-
tion nonclinical studies based on loss of exposure and/or the development of
immunogenicity-related adverse effects. While immunogenicity may complicate the conduct
and/or interpretation of data from nonclinical studies of biotherapeutics, in gene ral immuno-
genicity in nonclinical species is not predictive of immunogenicity in humans (Ponce et al.,
2009). Careful assessment of the mechanism of action of the biotherapeutic and its relation
to the development of antitherapeutic antibodies is warranted, however, as there are isolated
examples demonstrating translatability of imm unogenicity from nonclinical species to
humans (e.g., Kroenke et al., 2024); additionally, product- or process-related impurities in bio-
therapeutics (e.g., host cell proteins) may potentially induce immunogenicity irrespective of
species (Fischer et al., 2017; Lundahl et al., 2021).
In the event that there is no relevant species in which to evaluate the nonclinical safety pro-
file of a biotherapeutic candidate, the use of relevant transgenic animals expressing the hu-
man receptor, animal model(s) of disease, or a spe cies-specific homologous surrogate
molecule can be considered. These approaches require careful evaluation to ensure their
appropriateness and relevance to administration of the clinical candidate in humans. It is
important to recognize that although these approaches may be useful for hazard identifi ca-
tion, they are generally not useful for quantitative risk assessment (e.g., safety margin deter-
mination, clinical dose level selection).
For cell and gene therapies, species selection depends on consideration of several factors,
including comparability of physiology and anatomy between the nonclinical species and
humans and biological relevance of the animal model, permissiveness/susceptibility to infec-
tion by, and replication of, viral vectors or microbial vectors for gene therapy, tissue tropism
of the expressed payload, immune tolerance to a human cell therapy product or human trans-
gene expressed by a gene therapy product, feasibility of using the planned clinical delivery
system/procedure in the nonclinical species, and/or the ability to access the clinically rele-
vant anatomic site for product administration (FDA, 2013; ICH 2023; Moffit et al., 2022).
The use of multiple species (i.e., rodent and nonrodent) or of NHPs is not a defaul t for these
molecules; rather, the model used should be scientifically ba sed and discussions with Health
Authorities are encouraged to ensure that nonclinical study designs and program plans align
with regulatory expectations.
For vaccine candidates, the prevailing regulatory guidance recommends the use of a rele-
vant animal species that develops the intended pharmacological response, such as an im-
mune response similar to the expected human response (see Chapter 8). An additional
consideration in the selection of an appropriate nonclinical species in vaccine development
is the evaluation of novel excipients or adjuvants included in the clinical formulation (see
Chapter 8).
1. Overview of biopharmaceuticals and comparison with small-molecule drug development8
I. Development of biopharmaceuticals
Carcinogenicity assessment
Drugs that are intended to be used for prolonged time periods (i.e., 6 months or greater)
are expected to be assessed for the potential that their administration may cause cancer
(ICH M3; ICH S1A (ICH, 2009, 2022a,b). Other factors that are also relevant in determining
the need for carcinogenicity studies include the intended patient population, extent of sys-
temic exposure, and similarity to endogenous substances (ICH, 2022a, b). Historically, carci-
nogenicity studies have only been conducted for small molecule drugs and have typically
been conducted in rodents. As acknowledged in ICH S6(R1) (ICH, 2011), standard carcinoge-
nicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals. The
lack of cross-reactivity of most biologic drugs with rodents precludes the conduct of in vivo
carcinogenicity assessments; even for biologics with lower-order species cross-reactivity, long
term studies are often impossible due to the development of immunogenicity. Nonetheless, a
product-specific weight-of-evidence assessment of carcinogenic potential may still be needed
based on the factors mentioned above (ICH, 2011; Lebrec et al., 2016; Vahle et al., 2010).
The risk of tumorigenesis and carcinogenesis associated with cell and gene therapies de-
pends on several factors, including the vector (e.g., promotor activity, insertional mutagenesis
potential), genetic modification(s), or aspects of the preparation of genetically modified cells
(McBlane et al., 2018). The assessment of carcinogenicity of cell and gene therapies varies
depending on the nature of the product as well as on the requirements of regional health au-
thorities (Kurauchi et al., 2020); as with many other issues in biotherapeutics development,
discussions with Health Authorities are encouraged to ensure that nonclinical plans align
with regulatory expectations.
Carcinogenicity and genotoxicity studies are typically not required for vaccine antigens
and/or final formulations; however, particular vaccine components such as novel adjuvants
and additives may justify nonclinical assessment (WHO, 2005, 2014) as discussed in the dedi-
cated chapters on vaccine developmen t (see Chapter 8).
Best practices in toxicology program design in the wake of the
COVID-19 pandemic
The global COVID-19 pandemic led to the imposition of lockdowns in many countries and
a considerable curtailing of international travel. In 2020, China halted exports of NHPs, lead-
ing to a significant impact on biomedical research (Grimm, 2023). Together with the decrease
in availability of NHPs, the demand for NHP species increased to support critical pharma-
cology and toxicology studies of potential therapies to treat COVID-19. These factors collec-
tively resulted in a serious limitation to the conduct of nonclinical assessments of
biopharmaceutical drug candidates and to delays in the development of new medicines for
the treatment of diseases with unmet medical needs (Ackley et al., 2023).
To address the emergent animal supply situation, the US FDA issued guidance, which
remained in effect until the end of the COVID-19 public health emergency, that provided rec-
ommendations regarding species selection for the evaluation of nonclinical toxicology of
small molecule and biologic drugs (FDA, 2022). This guidance followed on numerous discus-
sions about species selection in other venues, which focused on efforts to implement the 3Rs
Best practices in toxicology program design in the wake of the COVID-19 pandemic 9
I. Development of biopharmaceuticals
of ethical animal use and ensure the most appropriate use of NHP species; the recommenda-
tions being discussed prior to the pandemic focused on dose level selection and number of
dose groups, group size, use of recovery animals, the need for concurrent versus virtual con-
trol groups, and reuse of biologics-exposed NHPs (Ackley et al., 2023; Chapman et al., 2012;
Mattis et al., 2022; Menochet et al., 2022; Sewell et al., 2016; Steg er-Hartmann et al., 2020). A
2022 survey of nonclinical scientists working at companies with membership in the Intern a-
tional Consortium for Innovation and Quality in Pharmaceutical Development (IQ Con-
sortium or IQ) and/or the Biotechnology Innovation Organization (BIO) revealed that
NHPs were being utilized more commonly than expected for nonclinical toxicology studies
of small molecules (Ackley et al., 2023) as well as FDA in their guidance document (FDA,
2022) strongly discouraged the use of NHPs for evaluation of small molecules without a
scientifically compelling rationale and suggested that they should be reserved for those pro-
grams for which no other nonrodent species exists. Rather than the NHP, the minipig may
prove useful as an alternate nonrodent spe cies, particularly for small molec ule drugs, as out-
lined in a thorough discussion by Bode et al. (2010). Ultimately, the justification of the
nonclinical species selected for nonclinical assessment is critical and emphasis should be
placed on thorough scientific rationale for the selection; when there are questions or consid-
erations that merit discussion, discussions with Health Authorities are encouraged to ensure
alignment.
Specific to the COVID-19 pandemic, a platform approach for the mRNA technology uti-
lized for vaccine development served to minimize the use of NHPs (see Chapters 8 and 9;
FDA, 2023; WHO, 2022). The platform approach supports clinical trials with the use of exist-
ing nonclinical toxicity data based on the predecessor vaccine for a particular platform, i.e.,
mRNA technology that can be changed while the same drug product formulation (e.g., lipid
nanoparticles) remains unchanged. Additional vaccine types (e.g., circular RNA, viral vector
RNA) have employed this platform approach and are discussed in Chapters 8 and 9.
Discussions about nonanimal alternatives to nonclinical safety assessment were common
prior to the COVID-19 pandemic, and the NHP shortage that began in 2020 seemed to super-
charge efforts in this area. In late 2022, the FDA Modernization Act 2.0 was passed in the US;
while this legislation does not obviate the need for animal testing to enable development of
new drug candidates, it specifically allows the use of nonanimal alternatives (i.e., new
approach methodologies [NAMs]), including cell-based assays, microphysiological systems,
and bioprinted or computer models, in sup port of drug and biological product applications.
In early 2024, attesting to the importance of NAMs development and implementation, the
FDA Modernization Act 3.0 was issued; this bill specifies, among other points, that a process
for the qualification of NAMs should be developed, that review of applications containing
NAMs should be expedited, and that FDA should submit reports to the US Congress detail-
ing the types of NAMs that have been qualified and the number of animals that have been
saved by the implementation of NAMs.
Work has been ongoing for well over a decade to develop in vitro approaches to evaluate
organ-specificefficacy and toxicity endpoints (Ewart et al., 2017), as evidenced by initiatives
including Tox21 (Lynch et al., 2024), the US federal research collaboration aimed at developing
efficient nonanimal methods for the prediction of the effects of chemicals on human health,
and the European Partnership for Alternative Approaches to Animal Testing (EPAA) (Cozi-
gou et al., 2015), the publiceprivate partnership focused on international cooperation toward
nonanimal alternative methods. While incredible technical progress has been made in
1. Overview of biopharmaceuticals and comparison with small-molecule drug development10
I. Development of biopharmaceuticals
developing a range of tools, they are presently used mainly as an adjunct to animal studies for
(bio)pharmaceutical drug development rather than as replacements for them; to date, there are
no predictive alternatives to in vivo general toxicology studies that allow identification of
appropriate clinical dose ranges and potential adverse effects (Avila et al., 2020). However,
global health authorities remain interested in nonanimal methods but require more data attest-
ing to the validity of the methods before they can be fully used as replacements to traditional
approaches (Avila et al., 2020, 2023). In particular, the FDA has encouraged the submission of
data from NAMs in regulatory packages to enable their development of experience with and
understanding of alternative approaches. The focus on these methods by governmental repre-
sentatives may hasten their development and deployment in a regulatory context.
Another are a of active investigation is the use of large, heterogenous, structured and un-
structured datasets of toxicology-related endpoints, which lend themselves to artificial intel-
ligence (AI) and machine learning (ML) approaches, and the use of these approaches to
improve human risk prediction and minimize the use of animals in toxicology research. Toxi-
cology studies were historically primarily observational; however, the availability of
advanced tools and high-throughput approaches has led to an explosion in the volume of
toxicology data, which are challenging to curate and analyze manually, processes, which
are prone to human error. Examples of AI/ML approaches include the mining of historical
data and peer-reviewed literature to understand potential exposure-response relationships
using natural language processing, and the automation of data cleaning, quality control,
and “hit-calling” using AI (Kleinstreuer and Hartung, 2024). Although these approaches
are only begi nning to be employed, they may be able to further streamline the development
of both small molecule and biologic drug development leading to a reduction in the use of
animals in toxicology studies and more efficient delivery of therapies to patients.
Current best practice in nonclinical toxicology study and program design for biotherapeutics
involves the evaluation of target biology/pharmacology and species cross-reactivity, consider-
ation of opportunities for the incorporation of in silico and/or in vitro tools/assays to inform
the design of in vivo studies or potentially to replace in vivo studies, consideration of class ef-
fects of molecules to inform in vivo study design and possibly to reduce study size (e.g., group
number and/or animal number, inclusion of recovery animals), and the use of AI/ML to un-
derstand and predict outcomes of exposures to substances. Scientists should utilize cross-
functional collaboration (e.g., with bioinformatics, CMC, drug safety, and clinical development
colleagues) to optimize the design of in vivo studies and should take advantage of opportu-
nities to discuss study/program design with regulatory authorities to ensure alignment and
the execution of the most streamlined studies. Many of these principles are also applicable to
small molecule therapeutics, particularly in the realm of NAMs and nonanimal alternatives
that may inform on the nonclinical safety of these molecules. Ideally, studies and programs
will use the least number of animals and advance the development of novel methodologies
while delivering medicines to patients safely and efficiently.
Classes of biopharmaceuticals
As outlined in the prior edition of this chapter, a number of distinct types of bio-
pharmaceutic molecules have been made through traditional and modern synthetic
Classes of biopharmaceuticals 11
I. Development of biopharmaceuticals
methodologies. The advent of recombinant DNA technology in the 1970s enabled production
of multiple products including proteins (e.g., protein and enzyme replacement therapies,
PEGylated proteins), monoclonal antibodies (e.g., mono- and poly-specific antibodies,
effector mutated antibodies), fusion proteins (e.g., Fc fusion proteins, immunotoxin fusion
proteins), and antibody-drug conjugates.
Since the prior edition, numerous advances in biotherapeutics have taken place. Perhaps
the most prominent recent application was the development of messenger RNA (mRNA),
protein subunit, and viral vector vaccines to treat SARS-CoV-2. These therapies have been
received by billions of people worldwide, preventing millions of deaths globally and enabling
the reversal of stringent pandemic restrictions. The success of these therapies highlighted the
critical role of biotherapeutics in the treatment of unmet medical needs.
Expanding on the subtype of mRNA therapy, other gene therapy approaches have been
extensively investigated over the past decade. The class of gene therapy collectively includes
molecules such as small interfering RNA (siRNA), micro RNA (miRNA), and inhibitory anti-
sense oligonucleotides (ASOs), which are designed to trigger the inhibition of genes, and
plasmid DNA, mRNA, small activating RNA (saRNA), and CR ISPR (clustered regularly
interspaced short palindromic repeats)/Cas systems, which are designed to increase or cor-
rect target gene expression.
Due to the complexity of biotherapeutic development and manufacturing, treatment with
a biotherapeutic is significantly more expensive than treatment with a small molecule drug.
The cost of biotherapeutic drugs has had a societal impact on the cost of health care in gen-
eral, and the availability of biosimilar molecules has the potential to significantly mitigate this
trend (Mulcahy et al., 2017; Kvien et al., 2022), potentially extending the possibility of treat-
ment to wider segments of the population and offering the possibility of treatments in lower
income, non-US/EU countries. In the US alone, the projected savings offered by the availabil-
ity of biosimilar molecules ranges from $54B to $250B. The healthcare and regulatory land-
scapes in various global regions have influenced the approval status of biosimilar
molecules. The EU was the first of the highly regulated regions to establish a regulatory
pathway for the approval of biosimilars; the first approval in the EU took place in 2006
(Omnitrope [somatropin]), and to date a total of 76 biosimilars have been approved in the
EU. The first such approval in the US occurred in 2015 (Zarxio [filgrastim-sndz]); to date,
an additional 40 biosimilar molecules have received US FDA approval.
Traditional monoclonal antibodies have been engineered with various modifications to
enable tumor-specific activity and limit normal tissue toxicity (e.g., masking antibodies),
improve vascular permeability and/or tissue penetration (e.g., Nanobodies and DARPins),
transit the nearly impermeable blood-brain barrier (Boado, 2022; Kouhi et al., 2021; Par-
dridge, 2017), and target multiple anti gens simultaneously to increase efficacy (e.g., multispe-
cific antibodies) (Elshiaty et al., 2021; Keri et al., 2024). Additionally, numerous strategies
have been employed to modulate the activity of therapeutic monoclonal antibodies via tar-
geted mutations in the Fc region (e.g., enhancing or eliminating effector function [antibody
dependent cellular cytotoxicity and/or complement dependent cytotoxicity] or modulating
half-life) ( Abdeldaim and Schindowski, 2023).
A hybrid small molecule and biologic approach yielded antibody-drug conjugates, or
“ADCs”, which are designed to deliver highly potent cytotoxic small molecules to c ancer cells
expressing a surface antigen, with subsequent internalization and often lysosomal release of
1. Overview of biopharmaceuticals and comparison with small-molecule drug development12
I. Development of biopharmaceuticals
the payload. The first ADC approval was Mylotarg (gemtuzumab ozogamicin) in 2000; it is
comprised of an anti-CD33 antibody linked to a calicheamicin, a DNA damaging agent. Since
then, multiple approved ADCs have leveraged microtubule inhibitor and topoisomerase 1 in-
hibitor mechanisms, such as Adcetris and Enhertu, respectively, for various hematologic and
solid tumor indications. Three addi tional ADCs were approved using payloads targeting
DNA (Zynlonta), a pseudomonas exotoxin (Lumoxiti), or a photoactivated membrane dis-
ruptor (Akalux). A variety of additional antibody, linker, and payload strategies currently be-
ing evaluated across the industry are driven by untapped therapeutic opportunities for ADCs
(Fu et al., 2022; Senior, 2024).
The field of immunotherapy has grown tremendously since publication of the first edition
of this book. The seminal publication by Chen and Mellman (2013) describing the cancer-
immunity cycle highlighted stimulatory and inhibitory factors and elucidated potential
targets to enhance antitumor immunity. One major type of immunotherapy is the class of
checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, and anti-CTLA4 monoclonal antibodies),
a number of which have been approved over the past several years (e.g., pembrolizumab, ate-
zolizumab, nivolumab). Pembrolizumab, in particular, has achieved blockbuster status with
34 FDA approvals to date across various indications and sales in 2023 of $25B. The safety pro-
file of checkpoint inhibitor antibodies is fairly well-understood and related to mechanism of
action, and as observed adverse effects are generally clinically manageable, these agents pro-
vide meaningful clinical benefit(Liang et al., 2020).
Prophylactic and therapeutic vaccines represent important tools in the public health
arsenal for treating infectious diseases, as well as unmet medical needs, across the general
population, including vulnerable groups such as infants and the elderly. Notably, the unprec-
edented development of novel mRNA vaccines in response to the COVID-19 pan demic and
approaches to streamline toxicity assessment are highlighted in subsequent chapters. Similar
to biologics, the nonclinical toxicity evaluation may be limited to one relevant species; how-
ever, depending on the mechanism of action of the vaccine, species selection is based on viral
replication (permissiveness) and/or a desired immune response rather than cross-reactivity
or pharmacological relevance of that species relative to humans. Often, the vaccine or adju-
vants contained in the vaccine formulation are novel and require a case-by-case approach
during development and therefore, communication with health authorities prior to initiating
a dedicated toxicity study is essential. The components contained within novel vaccines can
include synthetic peptides, purified/recombinant proteins, peptide conjugat es, protein com-
plexes, virus-like particles, live virus or bacteria, attenuated/inactivated virus or bacteria,
viral vectors, DNA and mRNA (see Chapter 8). To enhance the desired immunologic
response of a vaccine, adjuvants are sometimes included in the formulation (e.g., aluminum
salts, CpG oligonucleotides, monophosphorylated lipid A, saponins, and oil-in-water emul-
sions) (Dey and Srivastava, 2011) and need to be evaluated separately, if novel, in addition
to the novel vaccine therapeutic. Unlike both biologics and small molecules, PK assessment
is typically not included in toxicity studies as immunogenicity is a surrogate for exposure
and pharmacodynamic response. Ultimately, there is a fine balance between efficacious
immunogenicity and undesired proinflammatory responses or even autoimmunity, and the
safety of vaccines through determination of a no observed adverse effect level (NOAEL) is
key to development.
Classes of biopharmaceuticals 13
I. Development of biopharmaceuticals
Oncolytic viruses (OVs) are emerging as a class of anticancer immunotherapy that har-
nesses the ability of certain replication-competent viruses to infect and preferentially lyse tu-
mor cells while sparing normal cells and tissues. Following tumor cell lysis, a systemic
immune response is generated against the tumors and this response is effective in killing
even uninjected lesions (Malvehy et al., 2021). The first OV, talimogene laherparepvec (T-
VEC), was approved in the US in 2015 and subsequently gained approval in Europe,
Australia, and Israel (Shalhout et al., 2023). T-VEC employs Herpes Simplex Virus Type I
(HSV1), as does another OV, teserpaturev, that has been approved in Japan. Other approved
OVs use adenovirus (H101, approved in China; nadofaragene firadenovec, approved in the
US). OVs are typically administered directly into tumors or into tumor-adjacent locations
(e.g., intravesical administration for nonmuscle invasive bladder cancer), thereby limiting
the systemic toxicity resulting from treatment. Although OVs have been shown to be effica-
cious and generally have a favorable safety profile, they are live, replication-competent vi-
ruses and there are attendant logistical and biological safety considerations that must be
managed both in the manufacturing and clinical realms (Shalhout et al., 2023).
Significant investments and progress have been made in cell therapies. These therapeutic
approaches are promising because of their specificity, enabling more precise and personal-
ized treatment of serious diseases. A number of approaches have been employed spanning
a range of therapeutic areas including regenerative medicine, immunotherapy, and cancer
therapy. Chimeric antigen receptor (CAR)-T cell therapy has been the dominant platform,
in which T cells are engineered to express a chimeric antigen-recognit ion and T cell activating
receptor. These cells target and become activated to eliminate tumor cells directly and indi-
rectly, but also result in side effects such as cytokine release syndrome and neurotoxicity.
The first CAR-T cell therapies approved by the FDA, starting in 2017 were KymriahÒ for
acute lymphoblastic leukemia and YescartaÒ for diffuse large B-cell lymphoma, both target-
ing CD19-expressing cells. Four additional CAR-T therapies have been approved for specific
lymphomas and leukemias expressing CD19 or BCMA. Unfortunately, CAR-T therapies are
less effective in solid tumors due to insufficient targets and the nature of solid tumors. Ad-
vances in future CAR-T therapies are focused on improving specificity, decreasing tumor
escape, and controlling activity (Cappell and Kochenderfer, 2023; Dagar et al., 2023).
Overall, the multitude of biologics approaches employed to date has yielded many new
therapeutic options to patients in recent years, as well as offer protection to the general pop-
ulation to mitigate the global COVID-19 pandemic, with the promise of exquisite specificity
and efficacy. These advantages are balanced with enormous development costs as well as a
host of undesired effects. Nevertheless, future advances will continue to broach new avenues
within these and other biopharmaceutical modalities and as well improve on current limita-
tions intrinsic to each.
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