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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5703_Библиотеки_им_академика_М_И_Перельмана
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Omalizumab case study 121
AMG X case study 121
mAbY.1 case study 121
Summary 122
References 122
Further reading 129
Introduction
It is generally assu med that, unlike small molecule chemical entities, the intrinsic safety
profile of biotherapeutics (including cytokines, growth factors, antibodies) is well-
understood for several reasons. Biotherapeutics have high binding specificity to the intended
targets and low off-target promiscuity, low susceptibility for bio-transformation via drug
metabolizing enzymes, and high similarity to endogenous human proteins, especially since
recent molecular engineering techniques that minimize immunogenicity have become avail-
able. Indeed, nonclinical-to-clinical correlations for biotherapeutics generally support the util-
ity of nonclinical studies for predicting adverse clinical responses (Bugelski and Martin, 2012;
Martin and Bugelski, 2012; Gribble et al., 2007 ). Many of the observed adverse reactions with
biotherapeutics are related to the target biology and can be predicted based on the anticipated
pharmacology and through testing in nonclinical studies in pharmacologically relevant sys-
tems (Martin and Bugelski, 2012; Pol son and Fuji, 2012). Therefore, it is crucial to understand
the pharmacology of the intended biotherapeutic in the selected species, as well as to comple-
ment in vivo studies with relevant in vitro safety assessments for optimal scientific value and
hazard identification.
One shortcoming in nonclinical species is the low predictive value for clinical adverse re-
actions associated with immunostimulation and immunosuppression. This poor predictivity
has been attributed to interspecies differences in immune response pathways or drug-target
binding interactions; the absence of preexisting genetic conditions, diseases, or latent infec-
tions; and the absence of concurrent medications that may alter immune responses (Bumbaca
et al., 2011).
Predicting adverse reactions to biotherapeutics is further complicated by the rapidly
expanding array of modalities, which include traditional constructs (recombinant human
proteins and monovalent antibodies), antibody fragments (e.g., Fab, scFv), peptibodies,
antibody-drug conjugates (ADC), bispecific molecules (e.g., bispecific T-cell engagers; BiTEs),
and multispecific antibody constructs (See also Chapter 2). Because of this diverse nature, it is
prudent to rely on a risk-based strategy to protect patient safety on a case-by-case basis for
biotherapeutics. It is within this framework that the regulatory agencies rely on current sci-
entific knowledge, best practices within the industry, and a case-by-case approach that is
tailored to each therapeutic agent and specific subject population to evaluate the initial clin-
ical testing of a novel biopharmaceutical. Specific case examples, which are presented later in
this chapter, will provide some insight into how these concepts are applied.
4. Early de-risking strategy for biotherapeutics96
I. Development of biopharmaceuticals
Establishing a safety profile for biotherapeutics in discovery and early
development
As describ ed in ICH S6(R1) (2011) guidance, nonclinical safety studies of biotherapeutics
are designed in such a manner to mimic intended clinical use, which in turn will offer the
maximum likelihood of identifying potential toxicities and whether they are reversible. A
well-executed nonclinical program should (1) identify potential safety risks based on target
biology, pharmacologic effect, previous nonclinical and clinical experience from targeting
the same pathway, and the therapeutic modality itself; (2) identify a pharmacologically rele-
vant nonclinical species; and (3) support translation of nonclin ical data to estimate the antic-
ipated pharmacologic activity in human. It is incumbent upon the S ponsor to demonstrate
that the species used in the safety studies are suitab le models for human risk characterization
and pred iction (ICH S6(R1), 2011; Bussiere et al., 2009).
Table 4.1 identifies factors that differentiate such molecules from biotherapeutics directed
against relatively low-risk targets. Agents that have a pleiotropic mechanism with the poten-
tial for side effects (e.g., cytokine storm) or that by-pass physiological control mechanisms
(e.g., superagonists) are identified as examples of agents that deserve heightened evaluation
regarding potential translational risk from nonclinical to clinical testing. The EMA guidance
also presents a departure from no-observed-adverse-effect-level (NOAEL)-based methods for
establishing the starting dose for FIH trials when the therapeutic is considered a high-risk
agent. Rather, for high-risk agents, the FIH dose should be based on the minimal anticipated
biological effect level (MABEL) in humans with incorporation of appropriate safety factors.
General safety considerations related to biotherapeutics in discovery and early
development
Biotherapeutic modalities specific for a wide range of therapeutic targets and pathways to
treat human diseases, are undergoing a constant evolution. As summarized in Table 4.2, con-
ventional biotherapeutic approaches have been established using antibody and protein mo-
dalities, wi th a number of variations within each of these categories (Table 4.2 does not
include alternative methods relying on cell-, tissue-, or viral-based therapeutics, which are
considered out of scope for this review). From a safety perspective, each of these modalities
offer unique advantages and challenges related to the pathway interrogated, PK/bio-
distribution, opportunities to shape target specificity or cell-cell interactions, and safety.
Thus, nonclinical scientists should understand the inherent risks associated with a given mo-
dality as well as the target-associated liabilities in their evaluations of a given agent.
Target liability assessment
The initial step for a toxicologist conducting an early risk assessment may be to investigate
what is already available in the public domain, and to compare this information with the
intended pharmacology of the biotherapeutic. For biotherapeutics, many of the toxicities
can be attributed to exaggerated/extended pharmacology and these can often be identified
General safety considerations related to biotherapeutics in discovery and early development 97
I. Development of biopharmaceuticals
TABLE 4.1 Points-to-consider during development of biotherapeutics directed against high-risk targets.
Low-risk target High-risk target
Mode of action • Follow-on modality or target with MOA well
understood
• Clear pharmacological effect
• Target has linear or sublinear dose-response
relationship
• Monitorable toxicology/pharmacology
• Reversible side effects
• Poorly understood mechanism
• Pleotropic; systemic activity
• Threshold-dose response/steep dose response curve
• Lack of safety biomarkers
• Irreversible side effect
Properties of the
intended
biotherapeutic
• Low affinity to target
• Well established off-target profile/no off-target
• Novel modality and target
• High affinity and/or avidity to target
• Unknown off-target profile/risk for off-target binding
Intended patient
population
• Children, pregnant women
Nature of target • Target only present in disease state, not on normal
cells/organs
• Redundant, non-critical target
• Inherent risk of unintended targeting; critical biological effect
• Target expressed on cells associated with feedback loops
affecting large/critical organ systems
Relevance of
animal models
• Good structural homology, target distribution, and
signaling pathways compared to human
• Comparable pharmacological effects
• Well-understood predictive animal models for
pharmacology/toxicology
• Poor structural homology, target distribution, signaling
pathways, and pharmacological effects, or no relevant
nonclinical species.
• Animal models of limited relevance to pharmacology and
toxicology
Basis for first-in-
human dose
• NOAEL-based approach
• Healthy volunteers
• Utilize all available in vitro and in vivo data, including
receptor binding/occupancy, concentration-response
relationships, PK data in relevant species
• Apply appropriate safety factor
• MABEL-based approach
• Patient population likely
• Utilize all available in vitro and in vivo data, including
receptor binding/occupancy, concentration-response
relationships, PK data in relevant species
• Apply appropriate safety factor
4. Early de-risking strategy for biotherapeutics98
I. Development of biopharmaceuticals
through dissection of pharmacological mechanisms. During this exercise, the potential target
organs and toxicities will be identified based on the following:
Target biology: An important consideration when assessing target liability, is whether the
goal of the target modulation is to normalize a condition through inhibition or enhancement
of a pathway. A review of the literature for effects of modulating the target signaling pathway
should be conducted, and the ramifications of any physiological changes should be considered
in the context of both the nonclinical species and the human disease population. Pathway
network mapping can be used to identify downstream partners that may be impacted by mod-
ulation of the target (e.g., Ingenuity Pathway Analysis, KEGG, GeneGo etc). A general under-
standing and awareness of these upstream and downstream modulators will provide
additional perspective on potential liabilities. For example, if a receptor-ligand interaction is
disrupted, all other ligands, receptors and compensatory reactions that may be affected should
be considered. By evaluating murine knock-out or knock-in models, transgenic phenotypes,
disease models and/or the manifestations of known human mutations and polymorphisms
are other ways to gain knowledge about the biology of a target and understand physiological
activities that may be at risk. It is essential to consider how the target will be modulated to
decide whether the mutation data is relevant for understanding potential toxicities.
Competitive intelligence: Another important source for identifying potential liabilities comes
from publicly available information regarding similar molecules designed to affect similar or
related pathways. Information in the public domain may cover preclinical and clinical find-
ings. It is important to keep in mind any potential points of differentiation (e.g., modality or
TABLE 4.2 Intrinsic properties associated with various biotherapeutic modalities.
Modality Classes Structures Considerations
Antibody Antibody
fragments
Bi(multi)-
specific
constructs
Unmodified mAb
Fab, scFv
BiTEs, bispecific Ab,
diabody,
heterodimeric scFv,
tandem scFv,
minibody
• High-specificity protein targeting
• Fully human sequences minimize potential for antidrug
antibody responses
• Fragments may increase tumor penetration. Removal of Fc
region eliminates effector activity (mediated by Fc gamma
receptor binding) and increases clearance (via reduced
FcRn-mediated Ab salvage and smaller molecular weight)
• Bispecificity can improve avidity and engage multicellular
interactions (e.g., BiTEs)
Fc-modified
Ab
Effector modified
(deglycosylation,
altered primary
sequence), FcRn
modified
• Binding to Fcg receptors can elicit desired or undesired
effector activity of the antibody
• Binding to the neonatal Fc receptor (FcRn) can alter half-life
and (theoretically) can alter maternal-fetal transport
Other Fc-fusion proteins • Fc-fusion can reduce clearance (via FcRn and increased
size) and modify effector function
Non-Ab
Protein
Recombinant
protein
PEGylation and other
PK modification
• Used as replacement factors or as a mimic to supplement/
inhibit specific pathways
• Can be modified to augment potency, biodistribution and
clearance
• Immunogenicity (loss of activity, clearance, cross-reactivity
with endogenous protein)
General safety considerations related to biotherapeutics in discovery and early development 99
I. Development of biopharmaceuticals
specificity for closely related targets) to appreciate whether the potential liabilities are appli-
cable for the biotherapeutic candidate being develop ed.
Target expression in normal vs disease state: Differences in target expression in normal human
tissues and disease states should be thoroughly evaluated. Gene expression, in situ hybridi-
zation, immunohistochemistry, and flow cytometry analysis are example tools that can be
utilized. While expression does not solely predict risk, data identifying the distribution of
the target within specific cell types is particularly helpful for focusing detailed evaluation,
and to guide clinical monitoring. Despite poor correlation in predicting target organ toxicity,
in silico expression data can sometimes help understand mechanisms of on- or off-target
toxicity in specific organs/tissues during investigation of unintended adverse events.
In vivo studies
Frequently used nonclinical species include mouse, rat, rabbit, dog, (mini-)pig and
nonhuman primate. The species that is deemed relevant is most likely the species in which
the biotherapeutic interacts with the intended target and exerts its desired pharmacologic ef-
fect in a similar manner as in humans. It may also be helpful to know target expression levels
and tissue distribution in the nonclinical species compared with human patients when inter-
preting the findings from an in vivo study. Understanding the differences and similarities in
the biological pathway of the target in patients and nonclinical species is a critical aspect of
predicting any clinical risk. However, tolerability data from animal species alone is generally
not sufficient to establish an intended clinical dosing regimen because of potential interspe-
cies differences in receptor/target affinity, distribution, or potency. Furthermore, pharmaco-
logic and pharmacokinetic differences in biodistribution or clearance can make the translation
between the nonclinical species and humans difficult, and in vivo studies should be comple-
mented with in vitro assays when relevant, to form a thorough understanding of the risk
associated with the clinical trial. Uncertainty and a lack of knowledge regarding both inter-
species extrapolation of safety findings, mechanism of action of novel pharmacologic path-
ways and target biology has led to severe adverse events in FIH trials in the past, and
largely contributed to the cytokine storm incident with TGN1412 (Suntharalingam et al.,
2006). Typically, one rodent and one nonrodent species should be used for nonclinical safety
and toxicology studies (ICH S6).
For biotherapeutics designed to bind specific target domains, such as therapeutic anti-
bodies, nonhuman primate is often the only relevant nonclinical species. If so, the developer
is obliged to have strong scientific justification, as studies using nonhuman primates are
restricted (Directive, 2010/63/EU of the European Parliament).
The 3R initiative (Reduce, Refine, Replace) has been widely accepted by the industry, and
the developer should be diligent in designing in vivo studies to minimize the number of an-
imals used, and the number of studies conducted. New approach methodologies (NAMs)
replacing animal studies are encouraged by both FDA and ICH, and the translatability of
these methods to the patient setting should be assessed in parallel to in vivo studies to build
more learnings (Avila et al., 2020).
Early in vivo studies should be conducted in a relevant species and comprise dose-levels
that explore the clinically relevant range and above, for which an early understanding/pre-
diction of projected human efficacious dose/exposure is a prerequisite. Such an early in vivo
study could be conducted for exploratory reasons and/or to determine the doses for the
4. Early de-risking strategy for biotherapeutics100
I. Development of biopharmaceuticals
pivotal toxicity studies (e.g., dose range-finding (DRF) study). The early studies should
monitor standard blood components as biomarkers for critical organs such as liver, kidneys
and heart, and particular attention should be paid to those organs that have been associated
with increased liability in the target liability assessment.
Antibody-based modalities
As a class, antibody-based therapies include mAbs, bispecific or multimeric antibodies,
effector-modified antibodies, antibody fragments, Fc-modified peptides and proteins, multi-
specific constructs, antibody-drug conjugates (ADCs), and many other engineered constructs
that incorporate Fab or Fc components. These constructs modify or eliminate the Fab and/or
Fc arms of an antibody to modulate exposure (half-life and biodistribution) and effector ac-
tivity/immune stimulation and carry warheads to target tissues (Holliger and Hudson, 2005;
Jazayeri and Carroll, 2008; Baeuerle et al., 2009; Alley et al., 2010; Beck et al., 2010). ADCs are
discussed in more detail in Chapter 6. Amongst the “naked,” nonconjugated constructs, spe-
cific modality-associated toxicities are discussed for BiTEs and effector modified mAb as
example modality-related toxicities (see Chapter 2). In contrast to the target-associated toxic-
ities, intrinsic toxicities associated with a mAb may be predicted based on the specific
construct.
Monoclonal antibody therapies
Monoclonal antibodies (mAbs) have become a standard treatment for a number of dis-
eases due to their effectiveness and high target specificity. The highly selective target
binding and/or slow plasma elimination of IgG antibodies have been exploited in the clin-
ical evaluation (to date nearly 1200 antibodies h ave been in clinical trials) and marketing
authorization (w175 therapeutics) of a range of antibody-based therapies targeting many
diseases, including inflammation/aut oimmunity, cancer, osteoporosis, and other disor-
ders (Nelson et al., 2010; Nelson and Reichert, 2009; Kaplon et al., 2023). This high degree
of target-binding specificity greatly reduces, but does not eliminate, the potential for
nonmechanism-based toxicities. Such off-target toxicities are discussed later in this
chapter.
The choice of antibody format, as discussed below, is an impo rtant consideration for deter-
mining in vivo biological activity of a mAb therapeutic candidate, and com panies are further
modifying the Fc-region in an effort to “tune” effector activity. Whereas early generation
mAbs antibodies contained murine or chimeric (murine/human) sequences, modern thera-
pies are fully human, thus minimizing the potential for antidrug antibody reactions, which
may lead to reduced exposure, reduced activity, and immune-mediated toxicities (Harding
et al., 2010). As currently practiced, antibody development can include humanization of var-
iable domains, engine ering the constant domains for altered effector function or PK (e.g.,
neonatal Fc receptor, FcRn, binding), truncation/polyspecificity engineering (e.g., diabodies,
minibodies, IgG fusion proteins, bispecific antibodies, intrabodies), conjugation with cyto-
toxic payloads (chemotherapeutic agents or radionuclides), use of alternative selection tech-
nologies (phag e, ribosome, yeast-display), use of alternative production systems (mammalian
cell, bacteria, yeast, plant), and use of methods to increase stability and/or aggregation resis-
tance (Hansel et al., 2010; Dhama et al., 2020).
General safety considerations related to biotherapeutics in discovery and early development 101
I. Development of biopharmaceuticals
IgG antibodies are w150 kDa tetramers consisting of pairs of identical disulfide-linked
heavy and light chains (see Fig. 4.1). The ability of an antibody to simultaneously bind
two target antigens (i.e., bivalency) substantially increases the functional affinity and binding
retention time i.e., avidity (Holliger and Hudson, 2005). The Fab region provides highly se-
lective antigen binding, whereas the constant (Fc) region modulates both immune effector
cell activity (via Fcg receptor binding and complement activation) and antibody half-life
(via binding to the FcRn receptor, Table 4.3). Specifically, interaction between the Fc region
of human IgG (particularly IgG1 and IgG3) and FcgRs on effector cells can drive antibody-
dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis
(ADCP), whereas interaction with the complement component C1q can drive complement-
dependent cytotoxicity (CDC; Figs. 4.1 and 4.2)(Chan and Carter, 2010; Moore et al.,
2010). Separately, interactions between the Fc region and the FcRn (Kim et al., 1994; Kim
et al., 1995) establishes placental IgG transport (Brambell, 1966; Brambell, 1969; Firan et al.,
2001), regulates basal IgG serum concentration (Wani et al., 2006; Ghetie et al., 1996; Kim
et al., 2008), and recycles IgG in a pH-dependent manner (Jones and Waldmann, 1972; Rode-
wald, 1976). Early experimental evidence implicated the endothelium as the major site of IgG
catabolism, consistent with PK data suggesting protein catabolism via processes involving
close association with the intravascular space (McFarlane, 1957; Waldmann and Strober,
1969). Subsequent work has confirmed localization of FcRn to the endothelium, which ap-
pears to be an ideal candidate for regulating IgG catabolism and transport based on its estab-
lished pinocytotic activity and enormous surface area (>1000 m
2
) for conduct of ef ficient
catabolism (Ghetie et al., 1996; Junghans, 1997; Borvak et al., 1998; Santostefano et al., 2012).
Given the exquisite antigenic specificity of current antibodies, target-mediated toxicities
associated with the Fab typically reflect exaggerated pharmacology in the context of the
intended target and pathway modulation; however off-target effects of mAb mediated by
poly-specificity have been reported (Notkins, 2004; James et al., 2003; Otte et al., 2006; Sche-
erer et al., 2007; Wu et al., 2007; Bumbaca et al., 2011). In addition, recent data have demon-
strated rare off-target, species-specific hematological effects, including thrombocytopenia,
platelet activation, reduced arterial pressure, and loss of consciousness associated with a
mAb that remain incompletely understo od (Santostefano et al., 2012).
Effector modified antibodies
Selection of the IgG subclass of an antibody defines its interactions with Fcg receptors
(FcgR, Table 4.1) and thus the associated immune response, which can include immediate hy-
persensitivity, cytotoxicity, and immune complex-mediated inflammation (Nimmerjahn and
Ravetch, 2007). FcRs are a group of glycoproteins belonging to the immunoglobulin super-
family and are organized into classes, FcaR, FcgR and FcεR. They are mostly expressed on
leukocytes, and they are the class of receptors most relevant for the function of therapeutic
antibodies. Evidence demonstr ating a critical role of FcgR in mediating the therapeutic po-
tency of antibodies has been shown experimentally with FcgR-knockout models, use of Fc
glycoform or protein engineering to modulate effector function, and through observational
studies demonstrating greater therapeutic efficacy in patients with high affinity polymor-
phisms for FcgRIIIa (Lazar et al., 2006; Clynes et al., 2000; Cartron et al., 2002; Weng and
Levy, 2003; Dall’Ozzo et al., 2004; Repp et al., 2011; Schlaeth et al., 2010; Shields et al.,
2001
). These data drove current efforts to optimize clinical response toward therapeutic
4. Early de-risking strategy for biotherapeutics102
I. Development of biopharmaceuticals
FIGURE 4.1 Schematic representation of biobetter antibody formats being pursued for clinical development. (a)
Schematic structure of an IgG1 antibody with glycosylation sites at asparagine 297 (Asn-297) in CH2 domains
indicated by hexagons. The general structure of N-linked glycosylation is shown inset; core structures indicated by
solid lines and variable structures by dotted lines comprising of Fucose (Fuc), N-Acetylglucosamine (GlcNAc),
Mannose (Man), Galactose (Gal) or N-Acetylneuraminic acid (Neu5Ac). Glyco-engineering of antibodies can involve
defucosylation, which refers to the removal of core fucose to enhance Fc-mediated effector functions. (b) Schematic
structure of an antibody drug conjugate (ado-trastuzumab emtansine; Kadcyla) including N-maleimidomethyl)
cyclohexane-1-carboxylate (MCC) linker and maytansinoid 1 (DM1) payload. (c) Prominent bispecific formats in
development as discussed in the text including: Triomab or Trifunctional antibody, dual variable domain immu-
noglobulin (DVD-Ig), Dock-and-Lock (DNL) antigen binding fragments (Fabs), bispecific T cell engager (BITE), dual
affinity re-targeting (DART) molecule, Tandem diabody (tandAb) and immune-mobilizing monoclonal TCRs against
cancer (ImmTAC). Reprinted from Elgundi et al. (2017).
antibodies by modulation of Fc - FcgR interactions. For example, a variety of anti-CD20 mAbs
are under development or have been approved for use in lymphoid malignancies, each with
unique effector activities including ADCC, CDC, and direct binding activity that both modu-
late CD20 target interactions and cell killing (Robak and Robak, 2011; Gonzalez Barca, 2022;
Bock et al., 2022).
In humans, the FcgR family includes FcgR1 (CD64), FcgRII (CD32, including isoforms
FcgRIIa, FcgRIIb, and FcgRIIc), and FcgRIII (CD16, including isoforms FcgRIIIa and
FcgRIIIb). Homologs of these receptors were identified in mice and cynomolgus monkeys,
although the available data suggest both unique species-specific interactions across IgG sub-
classes and FcgR distribution on white blood cells (Nimmerjah n and Ravetch, 2007; Jacobsen
et al., 2011). These data suggest caution in the use of nonclinical species as models for the po-
tential activity (and safety) of Fc-modified antibodies without careful characterization.
Bispecific and multimer antibody modalities
Various Fab antibody constructs have been designed and engineered to achieve greater
target/cell selectivity, higher affinity and avidity, increased tissue penetration, reduced effector
activity, and increased pharmacological potency (Figs. 4.1 and 4.2; See also Chapter 2)(Holliger
and Hudson, 2005; Beck et al., 2010; Baeuerle and Wesche, 2022; Allen et al., 2021).
TABLE 4.3 Key functional characteristics of human IgG subclass antibodies.
Subclass IgG1 IgG2 IgG3 IgG4
Serum half-life (days) 21 20 7 21
FcRn
a
binding þþ þþ þ þþ
FcgRI
b
binding þþþþ e þþþþ þþþ
FcgRIIA
c
binding þþþ þ þþ þ
FcgRIIB
d
binding þþ þ þþ þ
FcgRIIC
e
binding þþ þ þþ þ
FcgRIIIA
f
binding þþþ þ/ þþþ þ
FcgRIIIB
g
binding þþ e þþ e
C1q
h
þþ þ þþþ e
a
FcRn is the neonatal FcR expressed on monocytes, macrophages, DCs, hepatocytes, epithelial cells, endothelium of small
blood vessesl, intestinal endothelium and placenta.
b
FcgRI (CD64) is the high affinity receptor for IgG expressed on monocytes, macrophages, neutrophils, eosinophils, DCs,
mast cells, platelets, microglia.
c
FcgRIIA (CD32A) is the low/medium affinity receptor for IgG expressed on monocytes, macrophages, neutrophils, eosin-
ophils, NK cells, platelets, microglial cells, Langerhans cells.
d
FcgRIIB (CD32B1) is the low affinity inhibitory receptor for IgG expressed on B cells and mast cells.
e
FcgRIIC (CD32B2) is the low affinity receptor for IgG expressed on macrophages, neutrophils, eosinophils.
f
FcgRIIIA is the low/medium affinity receptor for IgG expressed on NK cells, monocytes, macrophages, CD8 T cells.
g
FcgRIIIB is the low affinity receptor for IgG expressed on eosinophils, neutrophils, monocytes, macrophages, mast cells,
follicular DCs.
h
C1q is the first component of complement.
Adapted from Brennan et al. (2010).
4. Early de-risking strategy for biotherapeutics104
I. Development of biopharmaceuticals
FIGURE 4.2 CD3
þ
bispecific T-cell engaging antibodies exert function in hematological malignancies and recruit
immune cells into the solid tumor. The schematic depicts the mechanism of action of bsAbs in solid tumors (a) and
hematological malignancies (b). Besides, there shows partial fragments of antibody as well as the derivatives formats
constructed from them in diagram (c). Reprinted from Wei et al., (2022).
General safety considerations related to biotherapeutics in discovery and early development 105
I. Development of biopharmaceuticals
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