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IgG4 bispecific antibody that binds to hFIXa and hFX and forms a molecular bridge that
mimics activated factor VIII (FVIIIa) and can restore the function of missing FVIIIa. Because
emicizumab does not share any sequence homology with FVIII, hemostasis may be restored
in the presence of FVIII inhibito rs. The antibo dy has little to no potential to induce CDC or
antibody-dependent cellular cytotoxicity (ADCC). Emicizumab was shown to bind similarly
to the corresponding cynomolgus monkey coagulation factors, as such the cynomolgus mon-
key is a pharmacologically relevant species. Notable findings in 26-week toxicology studies
were those associated with the exaggerated pharmacology of emicizumab and included le-
sions at the injection sites (reddish patch at subcutis, hemorrhage, white cell infiltrate, edema,
in addition to some degeneration and/or necrosis) and hematological changes (increased D-
dimer and fibrin degradation products [FDPs]). There was no evidence of thrombi in the or-
gans and tissues examined (NDA/BLA Multi-disciplin ary Review and Eva luation, 2017). The
most common side effects with Hemlibra (which may affect 1 in 10 people or more) are itch-
ing or pain at the place where it is injected, joint pain and headache. The most serious side
effects, which may affect up to one in 100 people, are thrombotic microangiopathy (clots in
small blood vessels) and thrombosis (formation of blood clots in the vessels), including
cavernous sinus thrombosis (clotting at the base of the brain) and superficial vein thrombosis
(clotting in veins under the skin, usually in the arms or legs) with skin damage.
Ocular disease
Age-related macular degener ation
Case Example 8. FaricimabdantieAng-2 anti-VEGF:
Macular degeneration, an eye disorder that progressively destroys sharp, central vision,
etc., macular degeneration (AMD) causes leaky blood vessels to grow under the retina,
and excessive neovascularization, bleed, and fluid leakage from the abnormal blood vessels
result in rapid vision loss or even blindness in patients. Antiangiogenesis treatment, such as
Lucentis, Eylea, and Beovu, has been approved for treatment of this condition and has shown
significant improvement in visual acuity and prevention of vision loss. Though over 90% of
the patients can benefit from the treatment (i.e., maintain vision), eventually these patients
become resistant to the treatment. New therapies are needed to further improve the therapeu-
tic efficacy.
Faricimab (previously RG7716) is a novel antieAng-2/anti-VEGF bispecific antibody spe-
cifically designed for intraocular use. It is assembled using Roche’s CrossMAb technology
(Basel, Switzerland) and binds both VEGF-A and Ang-2 with high affinity and specificity.
The Fc region of faricimab has been engine ered to abolish binding interactions to Fc YR
and Fc Rn for reduced effector function and faster systemic clearance (Regula et al., 2016).
Faricimab is bound to full length Ang 2 with high affinity across species including human,
cynomolgus monkey, rabbit, and mouse. Faricimab is also bound with high affinity to the
rat receptor binding domain, Ang 2-RBD-Fc. Faricimab did not bind to full length human
Ang-1, whereas it bound Ang-2. Faricimab showed high affinity binding to VEGF121 in
humans and rats and VEGF165 in humans. The cynomolgus monkey, rhesus monkey, and
human VEGF121 share 100% sequence homology. Therefore, faricimab was not formally
2. Nonclinical development of monovalent and polyvalent biopharmaceuticals46
I. Development of biopharmaceuticals
tested for binding to cynomolgus monkey VEGF121. The Fc region of RO6867461 was
mutated to prevent binding to Fc receptors. In the nonclinical studies in the rabbit and mon-
key identified toxicities that included severe ocular inflammation (rabbit and monkey), coag-
ulative liver necrosis (rabbit), degeneration/necrosis of the myocardium (rabbit), and
minimal mixed-cell inflammation in the aorta (monkey). The ocular inflammation in the mon-
key appeared to partially reverse 42 days after the second dose of faricimab with anti-
inflammatory treatment. The nonclinical data support the ocular findings are primarily
related to development of an immunogenic response to faricimab and not a direct proinflam-
matory effect of faricimab. The antiangiogenic mechanism of action of faricimab is per se not
considered to impair immune surveillance. This is supported by data from the clinical devel-
opment program indicating that the achieved low systemic exposures to faricimab were not
associated with overt negative immune-modulatory activities on the innate or adaptive im-
mune system. In line with these results, toxicology studies in cynomolgus monkeys up to
6 months provided no evidence of any impact of faricimab on the immune system, that is,
for hematology examinations and histopathological examinations of lymphoid organs
(BLA# 761235, 2021). During clinical tests, faricimab has shown superior efficacy and safety
in patients with DME, as compared to Lucentis.
Bispecific antibodies of endogenous receptor ligands for CNS delivery of
biotherapeutics across bloodebrain barrier
In neurology, bispecific antibodies hold promise for the treatment of neurological disor-
ders, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurode-
generative conditions.
One of the major challenges in developing therapies for neurologic disorders is the limited
ability of drugs to cross the bloodebrain barrier (BBB). The BBB, which is formed by tight
junctions between endothelial cells to closely regulate the exchange of macromolecules be-
tween the systemic circulation and the CNS, represents a major challenge to the delivery
of biologi cs into the brain for treatment of neurological disease. It has been noted that passive
transfer of antibodies into the brain is both limited and dose-dependent, whereby a steady
state of [brain]/[blood] ratio of IgG is estimated to be 1:1000 (Reiber and Felgenhauer,
1987). To achieve therapeutic antibody levels in the brain, larger systemic doses may there-
fore be required and consequently limit potential treatment benefits due to dose-related sys-
temic toxicities and/or exaggerated pharmacology in the periphery. However, bispecific
antibodies can be engineered to have improved BBB penetration, allowing them to reach
the desired targets within the CNS. This enhanced brain penetration enables more effective
targeting of neurologic disease processes.
In general, strategies using reverse-mediated transcyt osis (RMT) for drug delivery to the
brain involve the generation of a complex between the drug of interest and a receptor-
targeting entity. This entity may be the endogenous receptor ligand, an antibody targeting
the receptor or a mimetic peptide ligand. These two components can be chemically linked,
or the drug can be incorporated in liposomes or nanoparticles decorated with the RMT-
targeting ligand (Jones and Shusta, 2007). Among the most studied targets for RMT in brain
endothelial cells are the transferrin receptor (Tfr), low-density lipoprotein (LDL) receptor and
Dual-targeting antibodies 47
I. Development of biopharmaceuticals
insulin receptor, for reviews, see (Lajoie and Shusta, 2015; Paterson and Webster, 2016). The
TfR pathway is one of the most studied candidates for RMT (Friden et al., 1991; Pardridge
et al., 1991). TfR mediates iron delivery into the brain via binding of diferric transferrin
and constitutive internalization of the receptor complex across the BBB. Efforts to utilize
the TfR as a transport system to increase brain uptake of antibodies have historically met
with limited success, predominantly due to the use of high-affinity anti-TfR antibodies that
yield only limited distribution of antibody in the brain (Moos and Morgan, 2001) and remain
primarily localized to the BBB vasculature. Recent studies using lower affinity anti-TfR anti-
bodies, however, show promise for realizing the potential utility of RMT in a therapeutic
setting (Yu et al., 2011).
Anti-TfR/BACE1 is an example of a bispecific antibody that utilizes receptor-mediated
transcytosis via TfR to shuttle large-molecular-weight antibodies across the BBB. This dual-
targeting antibody approach relies on monovalent (one arm) binding to TfR for enhanced up-
take and distribution in the brain and to b-secretase (BACE1) for therapeutic activity against
this Alzheimer’s disease drug target (Yu et al., 2011). BACE1 is involved in the processing of
amyloid precursor protein (APP) to amyloid-beta (Ab) peptide s, which are found in the am-
yloid plaques that are a pathological hallmark of Alzheimer’s disease (Hussain et al., 1999;
Sinha et al., 1999; Masters and Beyreuther, 2006). The presence of amyloid plaques could
eventually lead to altered synaptic neurotransmission, inflammatory responses (e.g., astro-
gliosis), and neurotoxicity (Hardy and Selkoe, 2002).
The anti-TfR/BACE1 bispecific antibody offers an alternative to dosing higher levels of the
bivalent anti-BACE1 antibody by utilizing the principle of RMT to improve antibody uptake
into the brain. To optimize properties of the anti-TfR arm of the bispecifi c antibody, the
same investigative group then conducted a series of studies to evaluate the role of affinity to
TfR in antibody distribution to the brain parenchyma (Yu et al., 2011). Results of these studi es
showed that high-affinity anti-TfR antibodies accumulate in BBB endothelial cells, while lower
affinity anti-TfR antibodies have improved brain uptake and distribution in mice when admin-
istered at therapeutic dose levels, likely due to an increased dissociation from TfR (Yu et al.,
2011). As predicted, by taking advantage of TfR-mediated transcytosis, a dual-targeting
anti-TfR/BACE1 can improve brain uptake of antibodies and thereby increase associated
BACE1 inhibition to reduce brain A b levels in mice and monkeys (Yu et al., 2011).
Kariolis et al. (2020) described the development of a novel BBB artificial transport vehicle
(ATV) that exploits RMT by TfR, based on the Fc domain of a human igG1 antibody that has
been modified to allow specific binding to TfR, fused to anti-BACE1 Fabs. Pe ripheral admin-
istration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in
substantially improved CNS uptake and sustained pharmacodynamic responses. These ATVs
are currently undergoing evaluation in the clinic.
In terms of crossing the BBB, ANG4043 also provided a new strategy to target Angiopep-2
(AN2) and HER2. An2 can bind to low-density lipoprotein receptor 1 (LRP1), which effec-
tively crosses the BBB through receptor-mediated endocytosis and is taken up cells express-
ing LRP1 (Regina et al., 2015) and reduces HER2-positive brain metastasis of tumors.
Although the ultimate translation of the above technologies into humans remains un-
known at this time, these results support the promise of this dual-targeting antibody technol-
ogy to enable improved delivery of targeted biopharmaceuticals into the brain for the
treatment of neurodegenerative disorders.
2. Nonclinical development of monovalent and polyvalent biopharmaceuticals48
I. Development of biopharmaceuticals
Combination therapeutics
Although PVBs are an attractive alternative to MVB mixtures, combination treatment with
MVBs remains a popular approach in the treatment of cancer and infectious diseases. Com-
bination of MVBs and/or PVBs is actively explored in the clinic for the treatment of cancer
and has received regulatory approvals (Zhu et al., 2021). Similarly, in infectious diseases, a
triple antibody cocktail has been approved for the treatment of Zaire ebolavirus (Markham,
2021). In addition to mitigation of development of resistance, the ability to engage multiple
targets and/or pathways with already a pproved drugs or in-development drug candidates
and experience with the mAb development technology to enable expedited drug develop-
ment is the rationale for this approach. Recently, this approach was successfully used to
develop treatment for SARS-COV2 virus of the COVID pandemic (Bebenek et al., 2022)
and is presented in the case study below.
Case study: SARS-CoV-2 antibody cocktail
In light of the COVID pandemic, parallel high-throughput efforts to generate antibodies
against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
were undertaken. Candidate individual antibodies with optimal epitope binding and highly
potent neutralizing activity were generated from mice, as well as from convalescent plasma.
An antibody cocktail approach decreased the potential for reduced efficacy caused by variants
arising from the spread of the pandemic. In addition, an antibody cocktail also addressed the
possible selection for viral escape mutants in response to pressure from a single-antibody
treatment.
The lead antibodies in the antibody cocktail (casirivimab and imdevimab, together referred
to as REGEN-COV) were chosen to simultaneously bind to distinct regions of the receptor
binding domain (RBD) of the spike protein. REGEN-COV was assessed for efficacy against
a wide range of spike RBD variants using both replicating and nonreplicating pseudovirus
platforms for neutralization studies and was found not to rapidly select for mutants (Baum
et al., 2020b). The in vivo efficacy of REGEN-COV was evaluated in a prophylactic treatment
and therapeutic treatment setting (before and after the exposure to virus) in rhesus macaqu es
at 25 and 150 mg/kg. Similar efficacy was noted in both treatment settings at 25 and 150 mg/
kg as determined by viral clearance kinetics (as determined by clearance of genomic RNA
[gRNA] and subgenomic RNA [sgRNA]) and reduction of incidence of interstitial pneumonia
as observed in the histological evaluation of lungs (Baum et al., 2020a).
Toxicology studies for REGEN-COV were designed to support both preventive and ther-
apeutic clinical trials. Single antibodies and the combination were tested through both intra-
venous and subcutaneous dosing routes providing flexibility for clinical trials. The pivotal
toxicology study was a 4-week repeat-dose study in cynomolgus monkeys with an 8-week
recovery. In addition to the standard nonclinical assessment, safety pharmacology evaluation
and extensive clinical pathology assessments were conducted. There were no adv erse effects
and the highest dose tested (150 mg/kg/each mAb, a total of 300 mg/kg of REGEN-COV),
was the no observed adverse effect level. Consistent with ICHeS6 guideline, the TCR studies
were conducted with both normal adult human and monkey tissues and selected fetal human
Combination therapeutics 49
I. Development of biopharmaceuticals
tissues. The lack of binding in fetal tissues supported enrollment of pregnant women in clin-
ical trials. A first-in-human dose was selected based on the available preclinical data and PK-
PD modeling and simulation.
Based on the encouraging results from the clinical trial with nonhospitalized patients, FDA
granted an emergency use authorization (EUA) in November 2020 for treatment of mild to
moderate COVID- 19 in high-risk patients. In effect , under the unique circumstances of a
pandemic, the discovery to late-stage clinical development including FDA regulatory review
was completed in <12 months by expediting the time from discovery to proof-of concept tri-
als, close collaborations with external partners, and regulatory agency acceptance that some
of the nonclinical wo rk was still ongoing or planned (Kelley, 2020; Baldrick, 2022).
Summary
As with many of the case studies presented in this chapter, drug developers are continu-
ally faced with the challenges of ensuring that new technology platforms associated with vali-
dated or yet-to-be-validated targets are safe and efficacious. The need to understand the
translatability of safety findings from nonclinical toxicology studies to the clinic will continue
to grow for these classes of biopharmaceuticals as more PVBs enter and progress in clinical
development.
From the perspective of selecting an appropriate animal species for nonclinical toxicology
studies, PVBs capable of binding to all target antigens in nonclinical species and humans at
similar affinity and eliciting similar pharmacologic activity increase the likelihood of predict-
ing potential clinical safety liabilities. In several of the TDB case examples reviewed, this was
a key challenge for the nonclinical development programs and, in many cases, resulted in a
focus on in vitro investigations. However, in some of the case examples reviewed, a more
robust nonclinical safety evaluation was possible due to target-specific binding in cynomol-
gus monkey, which provided relevant preclinical safety data to inform the development pro-
gram. In one of the case studies of dual targeting antibodies (MEHD7945A), the cynomolgus
monkey was considered to be a more appropriate species for toxicity evaluation based on
binding of both epitopes to monkey targets and also the translatability of EGFR inhibition-
induced skin toxicities from monkeys to humans.
Toxicities with CD3 bispecific T-cell engagers are often associated with exaggerated phar-
macology and/or on-target/off-tumor toxicity based on normal tissue expression of the
target. Cytokine release syndrome and its subsequent sequelae are not unexpected based
on the intended mechanism of action and resultant T-cell activation, but it is not consistently
observed for all target antigens. In nonclinical studies, step up dosing or adaptive study de-
signs may mitigate some of the acute toxicities associated with the initial acute phase
response, similar to strategies employed in the clinic (Staflin et al., 2020 ; FDA, 2023a,b;
Van De Vyver et al., 2021). The on-target/off-tumor toxicities are of spe cial concern for solid
tumor targets where the target antigen may not be tumor restricted. There are several molec-
ular factors which may influence the potency and tolerability of CD3 bispecific antibodies as
mentioned in the previous sections. These include target copy number, the specificCD3
target epitope, the epitope distance to the membrane or structural features of the formed
immunological synapse (Ellerman, 2019). Customizing the avidity or affinities of each target
2. Nonclinical development of monovalent and polyvalent biopharmaceuticals50
I. Development of biopharmaceuticals
arm can modulate the potency/safety profile with several examples associating higher CD3
affinity with reduced tolerability (Staflin et al., 2020; Haber et al., 2021; Leong et al., 2017).
Modulating the affinity and avidity of the targeting arms is likely molecule and target spe-
cific and not readily translated universally. Different cellular responses are potentially trig-
gered by different T-cell activation thresholds and could be part of a strategy to design
molecules that de-couple cell killing from cytokine secretion. Other challenges such as high
immunogenicity can limit the utility of longer term studies (e.g., epcoritamab) and limitations
of in vitro assessments for FIH dose selection should be considered in the nonclinical devel-
opment strategy. When toxicities are observed in the clinical programs, therapeutic interven-
tion or prophylaxis strategies may be utilized to mitigate certain clinical adverse events.
These are examples of the ability to move forward with development programs when toxic-
ities are clinically manageable.
Another point of consideration with dual-targeting antibodies is the potential for unique
toxicities when targeting multiple pathways. Will the combined inhibition/activation of mul-
tiple target pathways present an opportunity for uncovering enhanced or overlapping toxic-
ities? Would the use of a single-target comparator molecule be useful in teasing out
safetyeefficacy relationships for a bispecific antibody? Furthermore, the pharmacokinetics,
desired clinical route, and dosing schedule should also be considered when designing
nonclinical toxicology studies.
A growing number of dual-targeting antibodies are now on the market for varied indica-
tions such as hemophilia and age-related macular degeneration (AMD). Having demonstrated
the utility of ligand-targeted biotherapeutics to the CNS, the re will be an increasing array of bi-
specific biotherapeutics targeting CNS different from the entities described in this chapter.
Finally, the case study regarding the antibody cocktail for SARS-CoV-2 outlines streamlined
antibody drug development under the unique circumstances of a pandemic and may also offer
pointers to expedite antibody drug development, in general, on a case-by-case basis.
Overall, the successful development of these PVBs depends on the ability to determine and/
or predict potential safety liabilities from target combinations, the relevance of the animal spe-
cies for toxicity testing, early identification of potential translational biomarkers in nonclinical
toxicology programs to connect the safety and efficacy relationships. Finally, early engagement
with health authorities or regulatory bodies to aid in the refinement of the most appropriate
nonclinical development plan for a specific technological platform should also be considered
as we continue to push the boundaries of conventional biopharmaceutical development.
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