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nonclinical studies should be designed with a sufficient postdose recovery period such that it
allows for an assessment of the potential to recover from adverse findings. Recovery periods
must also consider the PK profile of the molecule. Biologics generally have longer half-lives
than small-molecule therapeutics due to their mechanism of elimination (Prueksaritanont and
Tang, 2012). Taking that into account, the scheduling of sacrifices or study termination of
nonclinical toxicity studies should be driven by the half-life of the molecule. More specifically,
the main study necropsy is ideally conducted in close proximity to the last administered dose
when drug levels are still high, and the end of recovery termination is conducted at a point
when the drug is cleared to below pharmacologically active levels and suffi cient time is
allowed for target organ toxicities to reverse.
In Phase I advanced cancer clinical trials, treatment of patients can continue beyond the
duration supported by completed nonclinical toxicology study(ies) according to the pat ient’s
response. Results from repeat-dose studies of 3 months in duration following the intended
clinical schedule should be provided prior to initiating Phase III studies in advanced/late-
stage cancer patients. For most anticancer pharmaceuticals, including biologics for indica-
tions covered under ICH S9, a 3-month toxicity study is considered sufficient to support
marketing. As with the 4-week repeat-dose toxicology studies, 3-month toxicology studies
for oncology biologics should incorporate evaluations of toxicokinetics, immunogenicity,
standard toxicology parameters, clinical and anatomic pathology, safety pharmacology,
and a recovery period of adequate length with consideration to reversal of adverse effects
and half-life of the compound. The frequency of evaluations should be guided by the findings
in the 4-week repeat-dose toxicology studies. If eventua l clinical studies in earlier stage can-
cers or in adjuvant settings following resection of cancer may be considered, then it may be
prudent to conduct a 6-month toxicity study in lieu of or in addition to the 3-month toxicity
study, depending on the timing of the development plan and availability of drug supplies.
Specialty toxicology assessments
Assessments for safety pharmacology, reproductive toxicity, and immunotoxicity should
also be conducted for oncology biopharmaceuticals in alignment with the recommended
guidance or if warranted by a specific concern related to the pharmaceutical (i.e., as driven
by a certain patient population such as women of childbearing potential, patients with car-
diovascular disease, etc.).
Safety pharmacology
Assessments of vital organ function, including cardiovascular, respiratory, and central ner-
vous systems, should be included in general toxicology studies and available before the initi-
ation of clinical studies, but stand-alone safety pharmacology studies are not required for
biotherapeutics to support studies in patients with late-stage cancer or advanced disease.
Developmental and reproductive toxicology (DART)
The evaluation of toxicity to reproduction should be conducted in pharmacologically rele-
vant species. According to ICH S6(R1) and ICH S5 (R3), when the clinical candidate is
11. Biological therapies for cancer356
III. Specialty biologics and indications
pharmacologically active only in NHPs, there is still a preference to test the clinical candidate
in NHPs as opposed to using a rodent surrogate in a rodent model. Developmental and
reproductive toxicology (DART) studies in NHPs can only provide hazard identification.
Separate embryoefetal development (EFD) and/or pre- and postnatal development
(PPND) studies, or other study designs (justified by the sponsor) may be appropriate, partic-
ularly when there is some concern that the mechanism of acti on might lead to an adverse ef-
fect on EFD or pregnancy loss. However, one well-de signed study in NHPs, which includes
dosing from day 20 of gestation to birth and then observation of the offspring during the
postnatal phase (enhanced PPND, ePPND) can be considered, rather than separate EFD
and/or PPND studies (Weinbauer et al., 2011; Skaggs et al., 2019). Per ICH S9 Q&A, if a
weight-of-evidence assessment of reproductive risk is conclusive, an in vivo NHP study
may be waived if scientifically justified (ICH S9 Q&A).
ICH S5(R3) gives further details on ePPND study design (e.g., group size, endpoints, etc.)
in Annex 1 Table 5. The updated guidance gives some additional information related to
DART assessment for severely debilitating or life-threatening diseases (SDLT) in Annex 2.
As discussed in Chapter 3: Regulatory Guidelines and their Application in the Nonclinical
Evaluation of Biological Medicines, the Guidance allows for the use of qualified alternative
assays as part of an integrated DART strategy for oncology. Thus, a negative result in the
alternative assay that is supported by a negative result in a definitive EFD in a second species,
may allow sponsors to avoid another definitive EFD study.
If no relevant animal species exists for testing the clinical candidate, the use of transgenic
mice expressing the human target or homologous protein in a species expressing an ortholog
of the human target can be considered, assuming that sufficient background knowledge ex-
ists for the model (e.g., historical background data). The ICH S5 (R3) Guidance states that use
of species-specific surrogates should be considered but that it may not be appropriate to
calculate safety margins relative human exposures.
When the weight-of-evidence (e.g., mechani sm of action, phenotypic data from genetically
modified animals, class effects) suggests there will be an adverse effect on fertility or preg-
nancy outcome, these data can provide adequate information to communicate risk to repro-
duction, and under appropriate circumstances additional nonclinical studies might not be
warranted. The ICH S5(R3) Guidance and the FDA Guidance (Nonclinical Considerations
for Mitigating Nonhuman Primate Supply Constraints Arising from the COVID-19
Pandemic) jencourage sponsors to engage Health Authorities in order to align on the plan
for DART risk assessment, especially in cases where no relevant toxicology species can be
identified and a weight-of-evidence approach is proposed by the sponsor (ICH S5(R3) and
FDA, 2022).
The timing of reproductive studies for oncology biologics for advanced cancers is driven
by ICH S9. Embryoefetal toxicity studies of anticancer pharmaceuticals should be available
when the marketing application is submitted, but these studies are not considered essential to
support clinical trials intended for the treatment of patients with late-stage or advanced can-
cer. The FDA Nonclinical COVID-19 Pandemic Guidance allowed for the possibility of spon-
sors performing DART assessments solely via weight-of-evidence approaches or pushing
timing to allow DART studies as part of a postmarketing commitment (FDA, 2022). The guid-
ance further discouraged the use of NHPs in toxic ity studies designed to assess fertility by
histopathology when fertility parameters can be assessed in rodents. With the end of the
Nonclinical studies and principles of study design 357
III. Specialty biologics and indications
COVID-19 public health emergency in May 2023, the FDA determined that the guidance
would not be reissued, and noted that most provisions were largely restatements of recom-
mendations in other FDA guidances (Brown and Wange, 2023).
DART studies are also not considered essential for pharmaceuticals that are cytotoxic to
rapidly dividing cells or that belong to a class that has previously been well characterized
in causing developmental toxicity. Some targeted biopharmaceuticals that are conjugated
to toxins or cytotoxic chemicals would potentially fit into this category. For bio-
pharmaceuticals, an embryoefetal toxicity study might not always be feasible. There may
be extensive public information available regarding potential reproductive and/or develop-
mental effects of a particular class of compounds (e.g., interferons) where the only relevant
species is the NHP. In such cases, mechanistic studies indicating that similar effects are likely
to be caused by a new but related molecule may obviate the need for formal reproductive/
developmental toxicity studies. In each case, the scientific basis for assessing the potential for
possible effects on reproduction/development should be provided. Potential differences in
placental transfer of biopharmaceuticals should also be considered in the design and interpre-
tation of developmental toxicity studies. Annex 1 of ICH S5(R3) provides a helpful compar-
ison of the advantages and disadvantages of various species for DART assessment, with
potential for immunogenicity, historical control data availability, and placental transfer
discussed.
ICH S5 (R3) indicates that for biopharmaceuticals intended for advanced cancer indica-
tions, fertility and early embryonic development (FEED) studies are not warranted (ICH
S5(R3)). As with the ICH S9 Q&A guidance that NHP studies to address DART hazards
should not be the default, early conversation with Health Authorities around proposed
DART risk assessment is strongly advised.
Genotoxicity and carcinogenicity
Given the nature of biologics and antibodies in particular, the standard battery of genotox-
icity studies is not usually required. These agents do not interact with DNA (due to their
size), the test cells do not contain the active receptor, and impurities in the preparations
are not organic chemistry by-products. If the standard validated species (mouse and rat)
do not have the receptor for binding with the molecule, genotoxicity or carcinogenicity
testing in these species would be meaningless. Further, genotoxicity studies are not needed
to support Phase I clinical trials for therapeutics intended to treat patients with late-stage
or advanced cancer. If healthy volunteers will be entered into the study, and there is a chem-
ical (i.e., a toxin, cytotoxic, and/or PK enhancer such as polyethylene glycol) conjugated to
the biopharmaceutical, limited genotoxicity testing of the chemical conjugate and/or linker
may be warranted and could include a reverse-mutation Ames test for mutagenicity.
Carcinogenicity studies are usually not warranted to support marketing for therapeutics
intended to treat patients with late-stage or advanced cancer. The appropriateness of a carcino-
genicity assessment for anticancer pharmaceuticals is described in the ICH S1A guideline (ICH
S1A, 1995). Biopharmaceuticals may be nongenotoxic, but they can have carcinogenic/tumor
promoting effects. Assessing this potential is usually quite different from the approach used
for small molecules, i.e., tumor promotion studies and special types of carcinogenicity studies
may be useful (ICH S6, 2011). At some point, a product-specificassessment(PSA)of
11. Biological therapies for cancer358
III. Specialty biologics and indications
carcinogenic potential should be submitted, which is based on the intended clinical population
and treatment duration, and examines the “weight of evidence” around whether the molecule
can be expected to present any carcinogenic risk. This document is developed throughout
development for discussion with regulators and is included in the marketing application.
Immunotoxicity
For anticancer pharmaceuticals, the evaluation of immune organs within general toxi-
cology studies is usually considered sufficient to evaluate immunotoxic potential and support
marketing (ICH S9, 2010). In the case of specific classes of oncology biopharmaceuticals, addi-
tional assessments may be warranted to show the presence or lack of specific toxicities. A sig-
nificant number of oncology biologic therapeutics in development are intended to stimulate
or suppress the immune system. Hence, a thorough assessment of their safety in toxicology
studies should also include analysis of immunotoxicological endpoints (e.g.,
T celledependent antibody responses, serum immunoglobulins, peripheral blood immuno-
phenotypes, plasma cytokines, etc.) within standard toxicology studies. The measurement
of cytokines can also be helpful to characterize pharmacologic activity and/or to provide sup-
port for other diagnoses (i.e., infection, infusion reaction, or specific cytokine release) during
the course of nonclinical toxicology studies. While there is no formal requirement for the in-
clusion of in vitro cytokine release assays (CRAs) in first-in-human enabling toxicology
studies, it has become routine as many oncology biologics are also immunomodulatory,
acting as either direct agonists or blocking negative signals to immune cells (Grimaldi
et al., 2016 ). In cases where targets are expressed on the surface of immun e cells or tissue,
CRA evaluation may be warranted as part of risk assessment prior to first-in-human trials.
When T cell engagement is central to the mechanism of action for an oncology therapeutic
(e.g., CD3 bispecific), evaluation as part of pharmacology and toxicology studies may be suf-
ficient (Kamperschorer et al., 2020). In conjunction with the National Institute for Biological
Standards and Controls, a reference antibody panel for qualification and validation of CRAs
has been established (Vessillier et al., 2020).
Antibody-dependent cytotoxicity (ADCC) can also be monitored and in some cases such
as targeted cytotoxics is desired for efficacy. This should be evaluated both in vitro and
within the context of toxicity studies where the target antigen of interest may not be present.
Incorporation of specific immunotoxicological evaluations, number of time points, and need
for any subsequent mechanistic studies should be guided by the pharmacology of the com-
pound. In cases where the compound either stimulates or suppresses the immune response,
changes in immunotoxicological parameters are intended effects, and inclusion of immuno-
toxicological evalu ations may be beneficial as they can be used to inform pharmacodynamics.
If a specific concern has been identified based on the target or toxicity profile in a specific or-
gan system, additional studies may be performed for follow-up.
Tissue-binding study
With the inclusion of the Q&A to ICH S9 in 2018, tissue cross-reactivity (TCR) studies were
generally deemed unnecessary for initiation of first-in-human trials or later in clinical
Tissue-binding study 359
III. Specialty biologics and indications
development of biologics intended for the treatment of advanced cancer unless there was a
specific cause for concern (see 2.6 of ICH S9 Q&A). In cases where there is a specific cause
for concern, the tissue cross-reactivity study can employ immunohistochemical methods to
examine binding of the clinical candidate to a standard panel of human tissues. While bind-
ing to specific tissues does not by itself provide information on in vivo activity, it is a useful
tool to understand target distribution in conjunction with results from toxicology studies. Ad-
vances in technology have also made alternatives to immunohistochemistry-based TCRs an
attractive tool for investigators. Protein and cell microarrays are increasingly utilized in the
assessment of off-target binding of monoclonal antibody based therapeutics just as the num-
ber of TCR studies has decreased along with their defaul t inclusion in first-in-human support-
ing packages for oncology indications (MacLachlan et al., 2021). Tissue cross-reactivity
studies or alternative techniques in nonclinical species are not required, but may be conduct-
ed if useful for confirmation of target expression and interpretation.
Table 11.1 summarizes the studies, timing, and special considerations for the nonclinical
development of oncology biologics. Schedules described do not specify recovery periods,
which should be incorporated into the study design and justified scientifically. The nonclin-
ical schedule includes rodents and nonrodents. In certain circumstances, as mentioned previ-
ously, alternative approaches can be appropriate (e.g., genotoxic drugs targeting rapidly
dividing cells). The schedules described in Table 11.1 should be modified as appropriate
with molecules with extended pharmacodynamic effects or long half-lives (e.g., mAbs). In
addition, the potential effects of immunogenicity should be considered when designing
studies (see ICH S6).
Pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD)
The pharmacokinetics (PK) of biologics is more complex than that of small-molecule ther-
apeutics. In general, biologic drugs are broken down in the liver, kidney, blood, and extravas-
cular sites of administration into individual amino acids and peptides and undergo a slower
clearance. As a result, many biologics such as mAbs have long half-lives, which range from
days to weeks. Newer biologic drugs such as antibody fragments have shorter intrin sic half-
lives, but are often modified to extend their PK profiles (Chen et al., 2012). Longer half-lives
translate to less frequent clinical and nonclinical dosing regimens, but can also mean persis-
tent effects, including adverse effects. Hence, a measure of total systemic exposures (AUC) is
considered more meaningful for biologics than C
max
as a measure of safety.
Prior to initiation of repeat-dose toxicology studies, it is beneficial to understand the phar-
macokinetics in single-dose studies. Data from PK studies can be used to guide the PK eval-
uation in repeat-dose studies. If performed separately, PK studies should use the same
formulation, concentrations, routes of administration, and dose volume to be used in toxi-
cology studies, as these factors can influence the absorption and distribution of biologic com -
pounds (Xu and Vugmeyster, 2012). The choice of nonclinical species can also significantly
influence pharmacokinetics. Systemic exposures, bioavailability, and half-life can vary greatly
between laboratory species and humans. For example, a comparison of pharmacokinetics of
an anti-neuropilin-1 antibody showed faster rates of clearance in humans similar to mice and
rats, but slower clearan ce in cynomolgus monkeys (Xin et al., 2012). To account for differ-
ences, dose, dose volume, site of administration, and dosing regimens in toxicology studies
11. Biological therapies for cancer360
III. Specialty biologics and indications
TABLE 11.1 Nonclinical studies for oncology biologic therapeutics.
Type of study Timing Special considerations
2 weeks Prior to first-in-human studies Single-dose studies may be sufficient. Lack of a
single-dose study (where a repeat-dose study is
included) often does not preclude clinical study.
3-month toxicity
study
Prior to engaging in clinical trials of
similar duration
The longest duration of nonclinical toxicology study
needed for advanced oncology indications is
3 months.
Clinical study duration may exceed duration of
toxicology study.
Tissue-binding
study
Not required for advanced cancer
biologics unless there is cause for
concern
May be useful in understanding nonclinical
toxicology or clinical findings
Other
Safety
pharmacology
Prior to phase I Usually assessed as a part of the general toxicology
studies and includes evaluation of vital organ
function, including cardiovascular, respiratory and
central nervous systems.
Reproductive
toxicity
Prior to filing marketing application or
agreed upon timing with health
authorities
EFD, ePPND, or other scientifically justified study.
May not be required if literature unequivocally
demonstrates a risk based on target and this is
denoted in the labeling.
Fertility Specific studies not required. See
ICHS5(R3) 2020 and ICH S9
Specific concerns based on target should be
addressed in general toxicity or specialized studies
on a case-by-case basis.
Immunotoxicity Prior to phase I for immunomodulatory
oncology compounds; for other
compounds on a case-by-case basis
Histopathology of lymphoid organs will usually
suffice for advanced oncology indications for non-
immune-related targets
Genotoxicity Not required Considered if a component of the therapeutic (e.g.,
conjugated cytotoxin, etc.) is expected to interact
with DNA or chromosomal material, and/or
genotoxicity may be expected based on mechanism
of action.
Cytokine release
studies
Not required but may be expected based
on target expression and/or mechanism
of action
Used to mitigate risk for certain targets that raise
concern for adverse cytokine release either through
binding to a cell surface receptor on leukocytes
(ADCC or direct engagement) or through
downstream signaling or other cellular interactions.
Assays used for cytokine release assessment are
highly diverse and subject to multiple
interpretations. Use of validated controls is helpful
in this regard.
Juvenile studies Not required Conducted only when human safety data and
previous animal studies are considered insufficient
Combination
toxicity studies
Case by case For advanced oncology indications, these are not
usually required unless there is a specific concern
Carcinogenicity Not required A product-specific assessment (PSA) of carcinogenic
potential should be submitted
Tissue-binding study 361
may need to be adjusted accordingly. Another variable that can influence pharmacokinetics is
novel binding sites identified in tissue cross-reactivity or in vivo toxicology studies. Apart
from having the potential to elicit unanticipated adverse effects, novel binding sites can
sequester the molecule (by acting as sinks) from the intended target and affect both its phar-
macokinetics and pharmacodynamics (Bumbaca et al., 2011). Given these variables, the
design of the PK assessment within the framework of toxicology studies cannot be predeter-
mined, and must be made on a case-by-case basis.
A complete assessment of pharmacokinetics in toxicology studies should include determi-
nation of parameters such as AUC, C
max
, bioavailability, and half-life. In repeat-dose studies,
the effects of multiple dosing (i.e., accumulation) should also be assessed. While many bio-
logics undergo target-mediated clearance, for others clearance mechanisms are dependent
on dose. Therefore, the length of recovery period should also be guided by PK considerations
in addition to toxicity considerations. A postdose recovery period of adequate length enables
not only an assessment of the reversibility of any toxic effects, but also an accurate calculation
of PK parameters such as half-life.
Since the pharmacokinetics of biologic therapeutics is tightly correlated with immunoge-
nicity profiles, a complete assessment of pharmacokinetics is not possible without evalu ation
for ADAs. Human proteins are inherently immunogenic in nonclinical species, and often
result in ADAs within days or weeks of administration (Baumann, 2008). However, the
immunogenic potential of biologics in nonclinical species is not predictive of the clinical sit-
uation (Bussiere, 2008; Caravella and Lugovskoy, 2010). Nevertheless, assessment of ADAs
should be considered a vital part of the safety evaluation of biologics. An immunogenic
response does not necessarily indicate that a thorough safety assessment cannot be conduct-
ed, but that safety data must be interpreted in the context of immunogenicity. Except in cases
where ADAs result in little to no exposure to drug, safety data are generally interpretable.
ADAs may have no discernible impact on exposure and efficacy in some cases, while in
others an immunogenic response may result in diminished exposures and half-lives, if the
ADAs are clearing, or inhibit biological activity and interfere with measurement of the
drug, if ADAs are neutralizing. If the safety evaluation necessitates a determination of the na-
ture of the immunogenic response, special assays may be considered to investigate whether
the ADAs are clearing or neutralizing. In the absence of an efficacy/pharmacodynamic
marker, assays to characterize neutralization potential of ADAs may be especially warranted
as an indirect read of interference with biological activity (O’ Conner, 2009).
Assessment of ADAs may be helpful in toxicology studies both during the dosing and the
recovery phases to correlate with inter-animal differences in pharmacokinetics and/or phar-
macodynamic responses. Oft en aberrancies in the PK profiles indicate presence of ADAs, and
prompt analysis, however the lack of detectable ADAs does not indicate absence of immuno-
genicity. Detection of ADAs may be contingent on the level of drug in serum. When drug
concentrations in serum are high, ADAs can form complexes with the drug and escape detec-
tion (assay interference), thus resulting in false negatives in the immunogenicity assay (Stu-
benrauch et al., 2010). It is recommended, therefore, that blood collection for immunogenicity
continue into the recovery phase because ADAs may be detected as the drug is cleared. While
an ADA response is expected and is not considered adverse, ADAs do carry the potential to
elicit toxic effects. ADAs have been known to induce complement activation, vasculitis, and
11. Biological therapies for cancer362
III. Specialty biologics and indications
anaphylaxis (Bria et al., 2008; Haller et al., 2008). Therefore, it is also prudent to evaluate tis-
sues for histopathological changes related to immune complex formation and deposition.
Unlike small-molecule therapeutics, the pharmacodynamics (PD) of biologics is not always
driven by PK, and PD responses do not always correlate with parameters such as C
max
(DeGeorge et al., 1998). Long half-lives and high affinities to target proteins often result in
long-lived PD responses that sometimes outlast detection of drug in serum. Since many bio-
logics such as mAbs do not elicit any toxic effects in nonclinical species, assays measuring PD
or biological activity should be included in toxicology studies to demonstrate biological ac-
tivity. A well-designed toxicology study should demonstrate biological/pharmacological ac-
tivity of the biologic drug during the dosing phase and incorporate a long enough recovery
period to show at least a partial reversal of the response measured. Since ADAs can limit
exposure and curtail biological activity, PD measurements provide a useful means to assess
exposure and efficacy throughout the study (Tib bitts et al., 2010). In the case that PD/effic acy
assays are not available, a characterization of the immunogenic response as clearing or
neutralizing may be warranted as an indirect read of continued biological acti vity in the pres-
ence of ADAs. Lack of neutralizing ADAs coupled with presence of drug in the serum (i.e.,
continued exposure) indicates availability of drug to interact with target. When possible, time
points for PD assessments should overlap with PK and immunogenicity time points, since
combined evaluation of all three parameters provides a full profile of the biologic drug
in vivo, and enables characterization of its exposureeactivity relationship.
The nature of the PD/activity assays and endpoints measured is dependent on the phar-
macological action of the drug, availability of assays, and ease of measurement. Since many
biologic drugs in oncology indications are intended to stimulate or suppress the immune sys-
tem, immunotoxicological endpoints (e.g., T celledependent antibody responses, peripheral
blood immunophenotypes, serum immunoglobulins, plasma cytokines, etc.) may be used as
a readout of biological activity. Yet for other compounds, a biomarker of efficacy in the blood
or urine may be considered more relevant. Within the field of oncology, there has been a
growing need for the demonstration of proof of mechanism. Biomarkers to demonstrate func-
tional (i.e., antitumor) efficacy (reduced tumor proliferation, cell death, etc.) are often identi-
fied early in nonclinical pharmacology studies and have been used in the selection of
appropriate animal species and lead compounds, and can be included in toxicology studies
(Maitland and Schilsky, 2011; Kummar et al., 2006). A major advantage of early development
of biomarkers of efficacy is that this inform ation can be used to glean a biologically efficacious
dose, and may aid in the decisions around dose and dosing schedule in the clinic. Moreover,
biomarkers evaluated in the nonclinical space may be translated to clinical efficacy to confirm
a drug’ s pharmacological action, guide protocol design, selection of patients, and minimize
safety risks (Floyd and McShane, 2004). A major disadvantage, however, is that clinically
relevant biomarkers may not be expressed in healthy animals, which are most often used
for toxicology studies. As a result, biomarker analysis in nonclinical studies may necessitate
ex vivo activation or manipulation of cells in culture in the presence of drug to induce or sup-
press a certain response (Hodgson et al., 2009). Regardless of the nature of the assay, mea-
surement of in vivo activity/PD responses provides information regarding biological
activity, which is one step beyond exposure information gleaned from pharmacokinetic anal-
ysis, and acts as an additional indicator of safety and efficacy of novel therapeutics (ICH S1A,
1995; Wate rton and Pylkkanen, 2012).
Tissue-binding study 363
III. Specialty biologics and indications
Nonclinical development of marketed biologics
A cross-section of marketed biologic therapies for use in oncology indications is shown in
Table 11.2. The nonclinical development of some of these different agents are summarized
and compared in the following section.
TABLE 11.2 Select list of marketed biologics for oncology indications.
Trade name Generic name Target/marker Other characteristics
Monoclonal antibodies
Tecentriq Atezolizumab PD-L1 Humanized IgG1
Avastin Bevacizumab VEGF Humanized IgG1 (93% human)
Bavencio Avelumab PD-L1 Humanized IgG1
Campath Alemtuzumab CD52 membrane
glycoprotein (CLL)
Humanized IgG1, depleting
Imfinzi Durvalumab PD-L1 Human IgG1k
Erbitux Cetuximab EGFR Chimeric
Herceptin Trastuzumab HER2 protein, p185
Mylotarg Gemtuzumab CD33 antigen with toxin
attached (calicheamicin)
Opdivo Nivolumab PD-1 Fully human IgG4
Keytruda Pembrolizumab PD-1 Humanized IgG4
Opdualag Relatlimab and
nivolumab in
combination
LAG-3, PD-1 Human IgG4 (both antibodies)
Rituxan Rituximab CD20 Chimeric, depleting
Soliris Eculizumab Complement protein C5
Vectibix Panitumumab EGFR
Yervoy,
Winglore
Ipilimumab CTLA4 Fully human IgG1, immuno-enhancer
Radiolabeled biologics
Bexxar Tositumomab,
I131
tositumomab
CD20 Single-course treatment, depleting
Zevalin Irbrutumomab CD20, yttrium-90
radiolabeled
11. Biological therapies for cancer364
III. Specialty biologics and indications
TABLE 11.2 Select list of marketed biologics for oncology indications.dcont’d
Trade name Generic name Target/marker Other characteristics
Recombinant enzymes
Elitek,
Fasturtec
Rasburicase Recombinant urate-oxidase
Elspar Asparaginase
L-Asparagine
amidohydrolase type EC-2
Oncaspar Pegaspargase
L-Asparagine
amidohydrolase covalently
conjugated to
monomethoxypolyethylene
glycol (mPEG)
Interleukins, interferons
Aranesp Darbepoetin alfa Modified recombinant
erythropoietin; differs from
recombinant human
erythropoietin in containing
5 N-linked oligosaccharide
chains, whereas
recombinant human
erythropoietin contains 3
chains
165-Amino-acid protein; 2 additional N-
glycosylation sites result from amino acid
substitutions in erythropoietin peptide
backbone
Epogen,
Procrit
Epoetin alpha Recombinant human
erythropoietin
165-Amino-acid protein;
Kepivance Palifermin Modified/truncated KGF Differs from endogenous human KGF in that
the first 23 N-terminal amino acids have been
deleted to improve protein stability
Leukine Sargramostim Recombinant human
granulocyte-macrophage
colony-stimulating factor
(rhuGM-CSF)
Produced by recombinant DNA technology in
a yeast (S. cerevisiae) expression system; differs
from natural human GM-CSF by a
substitution of leucine at position 23, and the
carbohydrate moiety may be different from
the native protein
Neuopgen Filgrastim Recombinant methionyl
human G-CSF
Neulasta Pegfilgrastim Covalent conjugate of
recombinant methionyl
human G-CSF (filgrastim)
and
monomethoxypolyethylene
glycol
20 kDa monomethoxypolyethylene glycol
molecule covalently bound to the N-terminal
methionyl residue of filgrastim
Neumega Oprelvekin Recombinant IL-11 Non-glycosylated; differs from the 178-amino-
acid length of native IL-11 only in lacking the
N-terminal proline residue. This alteration has
not resulted in measurable differences in
bioactivity either in vitro or in vivo.
(Continued)
Nonclinical development of marketed biologics 365
III. Specialty biologics and indications
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