Which animal species did regulators accept for approved monoclonal antibodies?

“The cynomolgus monkey was chosen as the relevant responder species and a comprehensive toxicology program was conducted with single- and multiple-dose studies up to duration of 6 months to characterize the overall safety of tocilizumab.”

“The cynomolgus monkey was chosen as the pharmacologically relevant species because tocilizumab cross-reacts with monkey IL-6R under in vitro and in vivo conditions.”

“The toxicity of crizanlizumab was evaluated in GLP-compliant 4- and 26-week toxicology studies in cynomolgus monkeys.”

“Crizanlizumab bound to human and cynomolgus monkey platelets expressing P-selectin, but did not bind to platelets expressing P-selectin from dog or rat. Thus, monkey is an appropriate toxicological animal model to study crizanlizumab.”

“Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab.”

“The IL-13 amino acid sequence homology between human and cynomolgus monkey is 95%, whereas that between human and rodent is 55% for mouse and 62% for rat. Tralokinumab did not cross-react with mouse IL-13.”

“The toxicology of aducanumab was adequately assessed in general toxicity studies in monkey and Tg2576 mouse.”

“Neither rat nor monkey is a particularly relevant species for general toxicity because of the lack of aggregated amyloid in rodent or non-aged monkey.”

“The pivotal, GLP-compliant toxicology studies were conducted in cynomolgus monkey, the only biologically relevant species”

“Erenumab has high affinity for the monkey and human CGRP-R, but not for rodent CGRP-R or closely related CGRP-R family members.”

“Because the shorter duration studies in rat and monkey demonstrated no toxicity, the chronic study was conducted only in cynomolgus monkey.”

“Fremanezumab is pharmacologically active in rat, rabbit, monkey, and human, as characterized in a series of binding and functional in vitro assays.”

“The rabbit was selected as efficacy species, the Cynomolgus monkey was selected as the nonrodent safety species and both species were used in pharmacokinetic/pharmacodynamic (PK/PD) assessment.”

“Characterisation of concizumab binding to TFPI showed high affinity, sub-nanomolar binding to rabbit, NHP and human TFPI with similar binding constants (KD of 0.22 nM, 0.06 nM and 0.04 nM for rabbit, Cynomolgus monkey and human, respectively).”

“The Applicant characterized the toxicity profile of garadacimab by conducting 4-week mouse and 26-week monkey toxicology studies with garadacimab using the IV and SC routes.”

“Garadacimab affinity is cross reactive with mouse, rabbit and cynomolgus βFXIIa (700pM, 400pM and 19nM respectively).”

“General toxicology studies were performed in rats and cynomolgus monkeys.”

“The study and peer review pathologists stated that the data demonstrated that both the rat and cynomolgus monkey were appropriate and relevant models for toxicity testing of ETI-204.”

“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”

“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”

“Toxicology studies were performed in cynomolgus monkeys and rabbits.”

“Cynomolgus monkey VEGF is predicted to have a protein sequence identical to that of human VEGF [41]. According to the applicant, bevacizumab also binds rabbit VEGF, although with a lower affinity than for human VEGF; the dissociation constant (Kd) is 8.0 nM for rabbit VEGF compared with 1.1 nM for human VEGF.”

“Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys.”

“The cynomolgus monkey was, however, a pharmacologically relevant species for toxicity testing based on a similar avelumab binding affinity to cynomolgus monkey and human PD-L1 and the comparable cross-reactivity of avelumab across cynomolgus monkey and human tissues.”

“The non-clinical toxicology program supporting belimumab development has been performed exclusively in the cynomolgus monkey (Macaca fascicularis) based on the following reasons:”

“The cynomolgus monkey was considered as the most relevant species in nonclinical studies since the monkey and human BLyS share 96.4% amino acid identity across the full length protein and 98% amino acid identity in the cleaved soluble portion of BLyS”

“Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans.”

“Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans.”

“The non-clinical safety programme consisted of a 1-month repeat-dose toxicity study in cynomolgus monkeys and tissue cross-reactivity studies in human tissues”

“Therefore, use of cynomolgus monkeys as the relevant animal species for the non-clinical in vivo program of nirsevimab is endorsed based on the comparable affinity of nirsevimab to human and cynomolgus FcRn and the fact that the YTE substitution decreases antibody exposure in rodents.”

“The only relevant species for nonclinical testing is the nonhuman primate.”

“The non-clinical evaluation has been conducted in the Cynomolgus monkey only since bimekizumab has no or very low affinity for mouse IL-17A, IL-17F or IL-17AF.”

“Therefore, cynomolgus monkey was determined to be the single relevant species for nonclinical evaluations.”

“Ublituximab binds with high affinity (low nM range) to CD20 on B cells from human and cynomolgus monkey. The product does not bind to rodent CD20.”

“The toxicology of caplacizumab was evaluated in single and repeat-dose toxicity studies in both rodent (guinea pig) and non-rodent species (Cynomolgus monkey).”

“Caplacizumab is cross-reactive to vWF in Cynomolgus monkey and guinea pig, but displays no pharmacological activity in rats, mice and dog.”

“Single and repeated dose toxicity studies were investigated in cynomolgus monkeys.”

“With respect to cynomolgus monkeys, the CHMP considered that although alemtuzumab was pharmacologically active in the species, the relevance of this species was limited due to species differences in the amino acid sequence for the CD52 antigen.”

“Based on the species specificity of target binding, the cynomolgus monkey has been selected as the main species for toxicity testing.”

“Certolizumab pegol did not bind TNFα from rodents, rabbit, guinea pigs and dog, but it inhibited TNFα from non-human primates, with at least a 1000-fold lower activity than against hTNFα.”

“Pivotal nonclinical studies were conducted in CD-1 mice and Cynomolgus monkeys; both were identified as relevant species in a series of pharmacology studies.”

“Reslizumab binds with similar affinity to human, monkey, and mouse IL-5 (KD = 24, 20, and 31 pM; respectively, as determined by BIAcore biosensor assays).”

“Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species.”

“Secukinumab crossreacts with cynomolgus, rhesus and marmoset monkey IL-17A, but not with rodent IL-17A, making the cynomolgus monkey the most appropriate nonclinical species.”

“Hence, rabbits and cynomolgus monkeys were used in the in vivo nonclinical studies.”

“it was shown to bind with similar binding affinity (KD~10-11 M) to human, cynomolgus monkey and rabbit FGF23. KRN23 shows no binding to mouse, rat or dog FGF23.”

“Ramucirumab binds only to human and non-human primate VEGFR2, thus a single species was used for the toxicological assessment of the antibody.”

“The Cynomolgus monkey can be considered an appropriate nonclinical species for ramucirumab toxicity testing given the comparable binding affinity of ramucirumab to its receptor in humans and Cynomolgus monkeys, and the fact that pharmacological effects have been seen in this test species.”

“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”

“Investigators reasoned that the use of nude rats rather than fully immune competent animals would allow for avoidance of the formation of anti-drug antibodies that would prevent long-term assessment of a human antibody in a rodent model.”

“The toxicology program for daratumumab consisted of a GLP 6-week repeat-dose toxicity study in chimpanzees, and in vitro tissue cross-reactivity studies using chimpanzee and human tissues.”

“Daratumumab binds to human and chimpanzee CD38, but not to CD38 of species typically used for nonclinical toxicology testing, ie, mouse, rat, rabbit, pig, and cynomolgus and rhesus monkey.”

“three pivotal repeat dose toxicity studies and an enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus monkey with REGN646 which is a fully human homologous antibody specific for cynomolgus monkey IL4Rα, and a subcutaneous fertility study in mice with REGN1103, a mouse homologous antibody that binds to IL4Rα.”

“Because dupilumab does not cross-react with species used to evaluate nonclinical safety, the sponsor developed a fully human homologous antibody, REGN646,”

“The ansuvimab-zykl nonclinical safety studies included a good laboratory practice (GLP) 4­ week, intravenous, repeat-dose toxicology study in rhesus monkeys”

“The activity of ansuvimab-zykl was evaluated in three in vivo proof-of-concept studies in which rhesus monkeys were challenged with uniformly lethal doses of Kikwit 8U EBOV (1000 pfu).”

“Thus, cynomolgus monkeys were selected as a single pharmacologically relevant species for use in nonclinical studies with lebrikizumab.”

“Lebrikizumab binds with pM affinity to IL-13 of human and cynomolgus monkey, but not IL-13 of mouse or rat.”

“The pivotal (GLP) subcutaneous (SC) toxicity studies (6-week + 9-week recovery, 3-month + 6-week recovery, and 6-month) were conducted in Sprague-Dawley rat and cynomolgus monkey.”

“Binding to monkey CGRP was not assessed because its sequence is identical to that of human CGRP; therefore, binding affinity was assumed to be similar in both species.”

“Due to the lack of a pharmacologically-relevant animal species to conduct toxicology studies, the scope of the toxicological evaluation for elotuzumab was limited to a tissue cross-reactivity study and in vivo studies that assessed the potential for off-target toxicity and local tolerance.”

“HuLuc63 specifically binds only to human CS1 and does not recognize CS1 from the mouse or any NHP species tested (see Figure 5).”

“The rat was chosen as the relevant animal species for the repeat-dose toxicity study, based on the rationale that systemic exposure of clesrovimab in the rats were sufficient to cover the anticipated clesrovimab exposure in humans.”

“It was therefore agreed that, as no relevant toxicological species exists and no off-target effects were expected in neither NHPs nor in rats, the use of the rat is supported from a 3R perspective in order to avoid unnecessary use of NHPs.”

“The cynomolgus monkey was the only nonclinical species demonstrated to be pharmacologically relevant, and the nonclinical program was conducted only in that species.”

“Sutimlimab binds cynomolgus monkey and human C1s with comparable affinity (EC50, 0.13 nM and 0.15 nM, respectively)”

“The pivotal studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”

“Satralizumab showed cross-reactivity in cynomolgus monkey but not in mice or rats. Based on these data, monkey was selected as the relevant species for nonclinical testing of satralizumab.”

“Toxicology studies were conducted with MLN0002 in two species (rabbit and Cynomolgus monkeys) by intravenous (IV) route to support the chronic use of MLN0002.”

“MLN0002 bound with similar affinity to leukocytes from rabbits, monkeys, and humans, but not from mice, rats, or guinea pigs.”

“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087). A 4-week study in Sprague-Dawley rats was also conducted (study 54167).”

“The Cynomolgus monkey was considered an appropriate species for safety testing of cetuximab. The similarity of adverse reactions seen in monkeys and humans supports this notion.”

“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent toxicology species as romosozumab binds to human, rat, and cynomolgus monkey sclerostin with similar affinity and is pharmacologically active in these species.”

“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent toxicology species as romosozumab binds to human, rat, and cynomolgus monkey sclerostin with similar affinity and is pharmacologically active in these species.”

“The toxicology profile of evinacumab was evaluated in rats, monkeys and rabbits, which are pharmacologically relevant nonclinical species”

“The cynomolgus monkey, rabbit, and rat are pharmacologically relevant species for toxicologic evaluation of evinacumab considering the high sequence homology (83-98%) to human ANGPTL3 and evinacumab target binding data”

“The pharmacokinetics of depemokimab have been assessed in the Cynomolgus monkey, which is the only species relevant for the toxicity studies.”

“The difference in the affinity of depemokimab for human IL-5 (KD 39.1pM) and cynomolgus IL-5 (KD 23.9pM) was around two-fold less compared to mepolizumab that has equivalent affinities for human and cynomolgus IL-5 of 54.2 and 55.4pM respectively.”

“Pivotal nonclinical studies were conducted in Cynomolgus monkeys.”

“Benralizumab binds to human and cynomolgus monkey IL-5Rα with KD values of 11 and 42 pM, respectively (as measured by BIAcore). Benralizumab did not cross-react with murine IL-5Rα.”

“In in vitro studies, emapalumab (NI-0501) bound to human (hIFNγ) and cynomolgus monkey IFNγ with similar affinity, but did not bind to rodent IFNγ, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“Emapalumab was cross-reactive to both cynomolgus and rhesus monkey, but no binding was detected in the dog, rat, or mouse.”

“Toxicology studies were conducted solely using cynomolgus monkeys because other species available for toxicity testing are not pharmacologically responsive to obinutuzumab.”

“Obinutuzumab binds to Cynomolgus monkey (but not rodent) CD20 with an affinity and ADCC potency similar to that of human CD20; consequently, the Cynomolgus monkey was considered the only appropriate species in which to assess the safety of obinutuzumab.”

“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”

“rodent p185neu (corresponding receptor protein to human p185HER2) is not recognised, whereas in non-human primates trastuzumab recognises a receptor (as yet uncharacterised) in epithelial cells.”

“The studies in cynomolgus monkeys are considered most relevant for human safety assessment.”

“In vitro, adalimumab is a potent inhibitor of TNFα from human, various primates including cynomolgus monkey, and dog (IC50s 10-10 –10-11 M). Neutralisation of murine TNFα was considerably weaker (>2.0 x 10-7), and adalimumab did not bind rat TNFα.”

“Toxicokinetics were evaluated as part of the RDT GLP studies in rats and Cynomolgus monkeys.”

“Marstacimab showed similar binding affinity to the combined K1K2 domains (via the K2 domain) of TFPI from human, cynomolgus monkey, rabbit, mouse, and the Wistar Han rat.”

“Toxicity of canakinumab was analysed in marmoset monkeys. Additional toxicity studies were conducted with the murine surrogate mAb 01BSUR in mice.”

“Canakinumab does not bind to IL-1β from mouse, rat, rabbit, or cynomolgus monkey. The only nonhuman species specifically recognized by canakinumab is the marmoset monkey.”

“Toxicology studies with tildrakizumab were conducted in cynomolgus monkeys which were shown to be a relevant species, based on the binding of tildrakizumab to cynomolgus IL-23p19.”

“Comparison of the amino acid sequences of IL-23p19 between human and various preclinical species revealed that cynomolgus monkeys had a 98% homology to humans.”

“Toxicology studies evaluating weekly IV (15-minute infusion) administration of nipocalimab were conducted in cynomolgus monkeys.”

“and pH 7.4 with KD of ≤57.8 pM, 58 pM for human and cynomolgus monkey, respectively and did not bind to mouse or rat FcRn.”

“The cynomolgus monkey was found to be the only pharmacological relevant nonclinical species for evaluation of local and systemic toxicities of durvalumab.”

“Durvalumab was found to only bind to human and cynomolgus monkey PD-L1, and the cynomolgus monkey was found to be the only relevant nonclinical species for the safety and toxicity studies.”

“These results support the monkey as the only pharmacologically relevant species.”

“At a concentration of 10 µg/mL, tremelimumab bound human and cynomolgus T cells treated with phytohemagglutinin (PHA) to stimulate expression of CTLA‐4, but did not bind mouse, rat, hamster, or rabbit PHA‐stimulated T cells”

“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1, supporting the use of cynomolgus monkey as the single pharmacologically relevant species for toxicity assessment.”

“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1”

“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing since only monkeys were identified as a relevant species for sarilumab in a series of pharmacology studies.”

“Sarilumab binds human and Cynomolgus monkey IL-6Rα with an equilibrium dissociation constant (Kd) of 54 pM and 123 pM, respectively, but no binding of sarilumab to the murine IL-6Rα was observed.”

“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”

“Its binding affinities to PD-1 derived from human and cynomolgus monkeys were comparable (~2X difference), however, the antibody did not bind to rodent or dog PD-1.”

“toxicity studies were conducted in cynomolgus monkey (6-week IV donanemab) to assess for any off-target toxicity, and in the PDAPP transgenic mouse model (6-week and 6-month SC mE8c, a murine surrogate) to assess for relevant on-target effects”

“Donanemab is not pharmacologically active in normal rodent or nonrodent; therefore, toxicity studies were conducted in cynomolgus monkey (6-week IV donanemab) to assess for any off-target toxicity”

“In in vitro studies, olaratumab bound to human and cynomolgus monkey PDGFR-α with similar affinity, but did not bind appreciably to mouse or rabbit PDGFR-α, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“In in vitro studies, olaratumab bound to human and cynomolgus monkey PDGFR-α with similar affinity, but did not bind appreciably to mouse or rabbit PDGFR-α, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey, the only pharmacologically relevant species.”

“Cynomolgus monkey IgG1 has a similar sequence to human IgG1 and cynomolgus monkeys were considered generally predictive of the pharmacokinetics of such antibodies in humans.”

“In in vitro studies, cemiplimab (REGN2810) bound to human and cynomolgus monkey PD-1 with similar affinity, but did not bind rodent PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“REGN2810 exhibited similar binding affinity for human and cynomolgus monkey PD-1 (see Table 2), but did not bind mouse or rat PD-1, supporting the use of cynomolgus monkeys as a pharmacologically relevant species for toxicity assessment.”

“Toripalimab does not cross-react with mouse or rat PD-1, so that toxicity studies were performed in cynomolgus monkeys, the only relevant species.”

“Toripalimab did not bind to the ECD of mouse or rat PD-1. On primary T cells, toripalimab had similar binding to human and cynomolgus PD-1 with EC50 values of 3.5 and 4.3 nM, respectively.”

“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”

“It is however agreed that it is likely that the monkey and human protein sequence are very similar, or even identical and a high activity on monkey VEGF is expected. For intraocular administration, this is considered sufficient.”

“The Applicant conducted GLP-compliant 6-week (doses up to 150 mg/kg/dose) and 13-week (doses up to 100 mg/kg/dose) repeat-dose toxicology studies of margetuximab in cynomolgus monkeys.”

“In a molecular binding study applying SPR, margetuximab Fc domain showed enhanced binding to activating cynomolgus Fc receptors CD16A and CD32A but also increased binding to inhibitory Fc receptor CD32B.”

“The safety of tafasitamab was evaluated in GLP-compliant 8- and 13-week general toxicology studies in cynomolgus monkeys.”

“Binding of tafasitamab-FITC to human, cynomolgus monkey and rhesus monkey lymphocytes was comparable. Tafasitamab showed lower binding to rat and mouse, and no binding to dog and rabbit lymphocytes.”

“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”

“No interactions were detected between nemolizumab and IL-31RA from mice, rats, or rabbits.”

“The in vivo toxicology of axatilimab was assessed in the cynomolgus monkey, the only toxicology species in which axatilimab binds to CSF-1R and blocks CSF-1-mediated signaling of the receptor.”

“The in vivo toxicology of axatilimab was assessed in the cynomolgus monkey, the only toxicology species in which axatilimab binds to CSF-1R and blocks CSF-1-mediated signaling of the receptor.”

“The nonclinical program with mepolizumab was conducted in Cynomolgus monkeys, which were determined to be the only pharmacologically relevant nonclinical test species.”

“The species specificity of mepolizumab was restricted to human and nonhuman primate IL-5 only. Mepolizumab did not bind to mouse or rat IL-5.”

“Toxicology studies of ocrelizumab were conducted in cynomolgus monkey, the only pharmacologically relevant species”

“Ocrelizumab specifically binds CD20 in humans and nonhuman primates. It does not bind CD20 in rodents. Therefore, cynomolgus monkey was selected as the relevant species for nonclinical investigation.”

“The toxicology package submitted by the applicant comprised studies in a single species (cynomolgus monkey) using the intended clinical routes of administration (intravenous and subcutaneous).”

“Similar binding kinetics were demonstrated for cynomolgus monkey IL-23 with a calculated value of 55 pM, however, the binding affinity for rabbit IL-23 was > 1000 fold lower and no binding to mouse or rat IL-23 was detectable.”

“The nonclinical toxicity studies of nivolumab were performed in a battery of nonGLP studies, and GLP- and ICH-compliant in vitro tissue binding studies in multiple species and in vivo toxicology studies in cynomolgus monkeys.”

“Nivolumab bound to PD-1 from humans and cynomolgus monkeys to a similar extent and blocked the interaction of PD-1 with its ligands. Nivolumab did not bind to PD-1 from rodents or rabbits.”

“repeat dose toxicology studies in rats up to 5 weeks and cynomolgus monkeys up to 27 weeks, reproductive and developmental toxicity studies in cynomolgus monkeys”

“In in vitro studies, penpulimab bound to human and cynomolgus monkey PD-1 but did not bind rodent PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“with EC50 values of 0.053 and 0.215 nM, respectively, but did not bind to mouse or rat PD-1, supporting the use of cynomolgus monkeys as a pharmacologically relevant species for toxicity assessment.”

“The Cynomolgus monkey was the preferred toxicity species based on the comparable in vitro human and monkey binding affinity and due to lack of binding to the rodent (mouse) ortholog, neu.”

“The amino acid homology of human and monkey ErbB2 was 99%. Therefore, the cynomolgus monkey was selected as the appropriate model for nonclinical evaluation.”

“Crovalimab was evaluated in good laboratory practice-compliant acute and chronic (6-month) toxicology studies in cynomolgus monkeys, which is the only pharmacologically-relevant species.”

“Crovalimab binds human C5 (hC5) and cynomolgus monkey C5 (cyC5) to the same extent (1.72 and 2.00 ×10-10 mol/L, respectively) and its binding is pH dependent. No binding to rat C5 (rC5) and a weak binding to mouse C5 (mC5) were detected.”

“Necitumumab bound to EGFR from humans and cynomolgus monkeys with similar affinity, thus, general toxicology studies were conducted in cynomolgus monkeys.”

“As indicated, the binding affinity for EGFR ECD is comparable between human and cyno. Lower affinities were achieved against rodent and rabbit isoforms.”

“Toxicology studies were only conducted in cynomolgus monkeys due to the limited cross reactivity profile of mogamulizumab.”

“Biotinylated mogamulizumab specifically bound peripheral lymphocytes from humans and cynomolgus monkeys only; most the specific binding was in the CD4-positive subset. Similar binding in humans and cynomolgus monkeys is expected given the CCR4 amino acid sequence at the mogamulizumab binding region is identical in humans and cynomolgus monkeys.”

“The Applicant identified the rat and monkey as pharmacologically relevant species for toxicology testing with alirocumab; both species express PCSK9, to which alirocumab binds with high affinity.”

“Alirocumab was shown to bind human and Cynomolgus monkey PCSK 9 with comparable affinity and lower affinity, but in nanomolar range to mouse, hamster, and rat PCSK9.”

“Toxicity studies with idarucizumab were performed in rats and rhesus monkeys. All studies in monkeys were conducted in the absence and presence of DE.”

“Dabigatran half-life of dabigatran is similar in rhesus and humans, while it is much shorter in rats. Furthermore, rhesus monkeys generate the active glucuronide metabolites of dabigatran, whereas in rats this is negligible.”

“Since denosumab recognizes and neutralizes RANKL in non human primates, the cynomolgus monkey was identified as a relevant species and the main studies have been conducted in ovariectomized animals.”

“This absence is acceptably justified by the fact that the RANKL domain to which denosumab binds is entirely conserved between cynomolgus monkeys and humans.”

“Drug safety assessed in human volunteers and in a battery of nonclinical studies in healthy rabbits and non-human primates showed no evidence of toxicity at the maximum proposed, single therapeutic dose of intravenous raxibacumab to be administered to human adults of 40 mg/kg.”

“several drug efficacy studies of raxibacumab with and without antibiotic in inhalation anthrax animal models (NZW rabbit and cynomolgus macaque)”

“A small number of chimpanzees, the only relevant species identified for safety testing, were given single or up to 5 once daily repeated doses of infliximab.”

“infliximab could neutralise human and chimpanzee TNFα with similar potency, while TNFα from a number of other species (rhesus cynomolgous, pigtail macaque, cotton-top tamarin, baboon, marmoset, pig, rabbit, rat and mouse) was not affected by infliximab.”

“The Applicant identified the hamster and monkey as pharmacologically relevant species for toxicology testing with evolocumab; both species express PCSK9, to which evolocumab binds with high affinity.”

“Evolocumab binds to human, cynomolgus monkey and hamster PCSK9 with high affinity (KD = 16, 8 and 14 pM, respectively; see Table 2).”

“For primary pharmacodynamics only experiments in non-human primates are relevant. Neither rodent nor canine B-cells bind rituximab.”

“such studies are unnecessary because B-cells in cynomolgus monkeys are lysed by a single dose of rituximab, which is evidence of relevant activity even if affinity and CD20 expression may be different in humans and primates.”

“The repeat dose studies were primarily performed in cynomolgus monkey, as the NHP was found to be the only pharmacological relevant species.”

“Affinity (KDs) for rozanolixizumab for mouse and rat FcRn was much weaker (nanomolar range) and binding to rabbit FcRn was not observed at all.”

“All in vivo toxicity studies were conducted in cynomolgus monkeys which can be considered as a relevant species for evaluation of safety of anifrolumab.”

“Cynomolgus monkey was selected as the pharmacologically relevant toxicology model for nonclinical safety assessment based on binding and neutralisation activity of anifrolumab in monkey cells.”

“The antibody does not bind to its target in animal species typically used in toxicology studies; however, a repeat-dose toxicology study in monkeys was conducted to investigate the potential off-target effects of isatuximab.”

“The antibody bound to human and chimpanzee CD38, but did not bind to CD38 from the mouse, rat, rabbit, pig, or cynomolgus and rhesus monkey.”

“Repeat-dose toxicity studies were performed in cynomolgus monkeys, because comparable potency was shown for brodalumab for the inhibition of monkey IL-17RA compared to human IL-17RA”

“because comparable potency was shown for brodalumab for the inhibition of monkey IL-17RA compared to human IL-17RA, whereas brodalumab does not cross-react with rodent IL-17RA and assessment of binding to dog IL-17RA was inconclusive.”

“An overview of the repeat-dose toxicity studies with golimumab in cynomolgus monkeys as well as the supportive study with the murine analogous molecule cV1q is given in Table 1.”

“The cynomolgus monkey was chosen as the most relevant non-clinical species, since golimumab showed little or no neutralization of dog, rabbit, mouse or rat TNFα.”

“Apart from the studies performed in primates, no toxicity studies in rodents or non-rodent animals except primates could have been carried out because of the species specificity of the antibody.”

“Simulect bound specifically to the α-chain of the primate IL-2-receptor, but not to the dog IL-2 receptor.”

“The cynomolgus monkey was the only relevant species due to insufficient cross-reactivity of risankizumab to IL-23 from rodents.”

“Binding of risankizumab to Cynomolgus monkey IL-23 was also high, with a dissociation constant (Kd) of less than 1 pM. Risankizumab bound to mouse IL-23 with a Kd of 15 nM.”

“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb).”

“Eculizumab did not effectively block haemolytic activity of sera from any primate or non-primate species tested, even at extremely high concentrations of antibody.”

“Spesolimab does not bind to IL36R in common nonclinical species. Therefore, BI 674304, a surrogate monoclonal antibody that specifically binds to mouse IL36R was developed to assess the pharmacology and toxicology of IL36R inactivation in mice.”

“spesolimab did not bind to IL36R from the mouse, mini pig, rhesus money, marmoset, rat, or hamster, and had very low affinity to IL36R from cynomolgus monkey.”

“The safety studies include repeated-dose toxicity with periods of recovery in cynomolgus monkeys, and developmental and reproductive toxicity studies in cynomolgus monkeys and mice; a number of non-pivotal studies was also conducted.”

“It was shown to have comparable binding and neutralising activity against human and cynomolgus macaque IL-12 and IL-23.”

“General toxicology studies, the embryo-fetal developmental study, and the enhanced pre- and post-natal developmental study (ePPND) were conducted in the cynomolgus monkey, a pharmacologically relevant species.”

“Siltuximab binds to and neutralizes human and non-human primate IL-6 but does not inhibit mouse, rat, dog, pig or guinea pig IL-6. Therefore, the cynomolgus monkey was selected as a pharmacologically relevant species for the toxicology and pharmacokinetics evaluation of siltuximab.”

“These results could be confirmed in Cynomolgus monkeys after a single administration of palivizumab.”

“The lack of repeated dose toxicity studies (including reproductive toxicity) was justified by the company by the immunogenicity of the human compound in animals and the lack of binding of the compound to a range of tissues.”

“Due to high anti-drug antibody (ADA) response in rats that reduced drug exposure, and combined with the apparent similarity in toxicity profile in rats and cynomolgus monkey, the cynomolgus monkey was selected as the single species for the pivotal 6-month toxicity study.”

“DX-2930 inhibits human, rat, and cynomolgus monkey pKal activity with comparable potencies (Table 2). Rats and cynomolgus monkeys are pharmacologically relevant species.”

“Toxicity of ixekizumab was evaluated in vitro and in vivo in Cynomolgyus monkeys; studies were justified in Cynomolgus monkeys on the basis that other species did not show pharmacological sensitivity to ixekizumab whereas this was similar between humans and Cynomolgus monkeys.”

“The results demonstrate that ixekizumab binds human and cynomolgus monkey IL-17 with similar affinities in a concentration dependent manner. Ixekizumab also binds to rabbit IL-17, but the affinity is lower and heterogenous. However, ixekizumab shows no binding to both mouse and rat IL-17.”

“The Applicant conducted repeat-dose toxicology studies in mice and Cynomolgus monkeys.”

“In vitro pharmacology studies demonstrated that atezolizumab binds to human, murine, and Cynomolgus monkey PD-L1”

“Toxicity studies were conducted in a single species, i.e. cynomolgus monkeys, based on comparable binding affinity and functional activity of teprotumumab to human and cynomolgus IGF-1R and lack of reactivity with rodent IGF-1R.”

“Toxicity studies were conducted in a single species, i.e. cynomolgus monkeys, based on comparable binding affinity and functional activity of teprotumumab to human and cynomolgus IGF-1R and lack of reactivity with rodent IGF-1R.”

“The toxicity of tislelizumab was assessed in several studies in cynomolgus monkeys, the relevant species.”

“From the results shown, tislelizumab seems to specifically bind to PD-1 (and to cynomolgus PD-1, but not to murine PD-1) with KD in the order of 0.1-0.2 nM.”

“Cynomolgus monkey was selected as the pharmacologically relevant animal model for non-clinical safety assessment”

“based on tezepelumab binding to human and cynomolgus monkey TSLP with picomolar affinity (KD vales of 15.8 pM and 32.2 pM, respectively)”

“The applicant submitted one single dose and one pivotal 5-week (IV/SC)/24-week (SC) repeat dose toxicity studies in cynomolgus monkey”

“Guselkumab demonstrated comparable species binding to IL-23 from humans, non-human primates (including cynomolgus monkeys), and guinea pigs, but only partial or no binding to dog, mouse, or rat IL-23.”

“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”

“Pharmacokinetic and toxicokinetic studies with ibalizumab were only performed in monkeys (Rhesus and Cynomolgus), because CD4 in other animal models is not recognized by Hu5A8.”

“Two cross-reactive species, the cynomolgus monkey and guinea pigs were used to”

“The following species are reacting with the antibody: Rhesus and cynomolgus monkey, pig, ferret, guinea pig, and dog. Lymphocytes from rat, gerbil, hamster, rabbit, or marmoset monkey are not reactive.”

“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”

“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”

“the murine surrogate molecule BB5.1 was administered to mice due to lack of pharmacologic activity of ALXN1210 in mice.”

“Neither ALXN1210 nor eculizumab exhibit detectable pharmacological activity against any non‐human species tested, as was predicted by epitope mapping studies and sequence alignments of human and non‐human C5 molecules, and confirmed by in vitro binding and activity studies.”

“Animal studies exploring the safety of dinutuximab were conducted in Sprague Dawley rats and cynomolgus monkeys.”

“Though there were no histopathological indications of an effect of dinutuximab on peripheral nerves in this study, ch14.18 has been shown to bind to GD2 in rats.”

“the cynomolgus monkey (Macaca fascicularis) was the only pharmacologically relevant animal species for the assessment of pharmacokinetics (PK) and toxicology.”

“cosibelimab selectively binds to monkey and human PD-L1 with high affinities, but not to murine PD-L1.”

“Therefore, toxicology studies were conducted using a transgenic mouse model expressing human CD19 (huCD19 Tg).”

“Inebilizumab binds specifically to human CD19 and shows no cross-reactivity for CD19 in nonhuman primate, rodents, or rabbits. Therefore, the species selected for nonclinical testing was the human CD19 transgenic mouse model (huCD19 Tg), which was considered the only relevant species.”

“Repeated dose general toxicity studies were conducted using intravenous administration of panitumumab to male and female cynomolgus monkeys.”

“Cross reactivity supported the choice of the cynomolgus monkey for safety testing.”

“Thirteen- and 26-week repeat-dose toxicity studies were conducted with pozelimab in cynomolgus monkeys. As pozelimab is not pharmacologically active in rat or mouse, it was not evaluated in a rodent species.”

“Pozelimab (REGN3918) is a human monoclonal antibody that binds with high affinity to complement factor 5 (C5) from human and monkey but not mouse, rat, or rabbit.”

“Given >99% homology with human APRIL and comparable binding affinity, the cynomolgus monkey was considered a pharmacological relevant species for safety evaluation.”

“In cross-species comparison studies, binding affinity for APRIL was comparable between cynomolgus monkeys, rabbits, and humans whereas binding to APRIL could not be detected in rodents (mouse or rat).”

“Toxicity studies with eptinezumab were conducted in rats, cynomolgus monkeys and rabbits. These species are considered pharmacologically relevant based on the affinity and functional activity of eptinezumab against CGRP from these species.”

“Eptinezumab has high affinity and specificity for rat, rabbit, monkey, and human α- and β-CGRP without off target binding to amylin, calcitonin, adrenomedulin, or intermedin/ adrenomedulin-2.”

“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”

“Flow cytometry binding was observed for a mouse CLDN18.2 ortholog (KD=2.6 nM) and cynomolgus monkey (KD=2.22 nM).”

“Two pivotal repeated-dose toxicity studies were performed in Cynomolgus monkeys”

“The Cynomolgus monkey was chosen as model to predict human pharmacology and toxicology since omalizumab binds Cynomolgus and human IgE with similar affinity but does not bind non-primate IgE.”

“including safety pharmacology studies, repeat-dose toxicity studies in mice and monkeys for durations up to 4 and 26 weeks, respectively, reproductive toxicity studies in mice and rabbits”

“OMS721 displayed functional activity in mouse, rabbit, and cynomolgus monkey, with potencies 3.8, 2.7 and 10-fold less than human. No functional activity was observed in rats.”

“The cynomolgus monkey was selected as the toxicology species because ipilimumab binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other traditional toxicology species (mouse, rat, rabbit), and has pharmacologic activity only in primates.”

“The cynomolgus monkey was selected as the toxicology species because ipilimumab binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other traditional toxicology species (mouse, rat, rabbit), and has pharmacologic activity only in primates.”

“General toxicity studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”

“DAC-HYP had no pharmacological effect on primary lymphocytes isolated from rats or mice. Plasmon surface resonance revealed comparable affinity of DAC-HYP for human (KD = 0.49 nM) and monkey (KD = 0.42 nM) CD25.”

“Nonclinical toxicology studies with bezlotoxumab and actoxumab, alone and in combination as bezlotoxumab + actoxumab were performed in mice.”

“This is acceptable as there is no species in which target-mediated toxicity can be investigated.”

“In vitro studies showed retifanlimab bound to human and cynomolgus monkey PD-1 with nanomolar affinity (0.6 and 3.6 nM, respectively) and did not cross react with rodent or canine PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”

“In vitro studies showed retifanlimab bound to human and cynomolgus monkey PD-1 with nanomolar affinity (0.6 and 3.6 nM, respectively) and did not cross react with rodent or canine PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”