HCP | Theracim

Section for Healthcare Professionals


1. Overview

TheraCIM (Nimotuzumab) is a humanized monoclonal antibody directed against human EGFR. TheraCIM binds with intermediate affinity and high specificity to the extracellular region of EGFR results in a blockade of EGF binding and EGFR pathway activation.

Properties of TheraCIM in killing cancer cells :

  • Antiproliferative activity.
  • Antiangiogenic activity.
  • Pro-apoptotic activity.
  • Mediates complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) activity.
  • Radiosensitizer activity

2. Attributes

Less immunogenic than the murine antibody
The humanized antibody is remarkably less immunogenic than the murine antibody.


Lower incidence of hypersensitivity
Hypersensitivity reactions are rare after nimotuzumab treatment, due to a low anti-idiotypic response to the antibody.

Pre-medication for hyper sensitivity is generally not required.


Intermediate affinity binding
TheraCIM binds to EGFR with intermediate affinity 108 and 109 M causing high tumour uptake and low uptake in normal tissue. This results in effective EGFR blockade without causing deleterious effects on the skin, because the optimal dose is far lower than the toxic dose.


Good safety profile: Pre-laboratory monitoring before TheraCIM is generally not required
Well tolerated: In particular indications, TheraCIM can be use in longer duration for than standard duration for mainstay therapy.


Simple dosing (parallel with icon)
TheraCIM is administered intravenously for 30-60 minutes.
TheraCIM does not need a loading dose.
TheraCIM has standard dose per patient .

3. Pharmacokinetics and pharmacodynamics of TheraCIM.

The PK profiles of TheraCIM have been investigated after administration of single or multiple intravenous (i.v) doses in cancer patients. TheraCIM was administered as monotherapy (study IIC RD EC-035, DE766-A-J101 and HH-2004/2) or in combination with concomitant chemotherapy (DE766-A-J201/08-TH-8201 and HH-2004/2). The studies were conducted in solid tumors (IIC RD EC-035) and (DE766-A-J101), in gastric tumors (DE766-A-J201/08-TH-8201) and recurrent or metastatic pancreatic cancer patients (HH-2004/2). Intravenous infusions of TheraCIM exhibited non-linear PK at weekly doses ranging from 50 mg to 800 mg. TheraCIM clearance decreased with increasing doses to 400 mg then appeared to plateau.


No metabolism or mass-balance studies have been performed and it is our understanding that this can be acceptable since biotechnology-derived pharmaceuticals are expected to degrade into small peptides and individual amino acids [1].


Two studies were performed to evaluate the pharmacodynamics (PD) of TheraCIM: Study IIC RD EC-076 and Study DE766-A-J201/08-TH-8201. TheraCIM pharmacodynamics activity is thought to occur via binding to EGFR, which prevents stimulation of the receptor by endogenous ligands, resulting in the loss of EGF activity. Binding of TheraCIM to the EGFR also results in internalization of the antibody-receptor complex, leading to the downregulation of EGFR expression, a mechanism that is consistent with other EGFR-targeted antibodies [2]. Consequently, the mechanism of clearance of TheraCIM is reported to be via internalization of the nimotuzumab-EGFR complex primarily on tissues with high to moderate EGFR expression, for example, tumors, hepatocytes and skin [3].


Study IIC RD EC-035:Pharmacokinetics parameters were obtained from 10 patients.


Plasma disappearance curves of the humanized anti-EGFR antibody TheraCIM were best fit by a bi-exponential equation with Pharmacokinetic details as followed:

The PK parameters determined using compartmental analysis suggests that TheraCIM shows non-linear behavior for the dosage levels of 50 and 200 mg. The AUC and elimination half-lives increased linearly with dose, while increasing concentration of the antibody lead to a decrease in plasma clearance between the doses of 50 and 200 mg [4].


Study DE766-A-J101: The serum DE-766 concentration after the first treatment on Course 1 reached maximum upon the completion of treatment (5 minutes after the infusion) at all doses, and decreased moderately. The increases of Cmax and AUC0-inf were more than proportional to dose. The extent of change in CL at 200 to 400 mg was smaller than that at 100 to 200 mg. VD was comparable with plasma volume. TheraCIM decreased dose-dependently, and the extent of decrease Lfrom 200 to 400 mg was smaller than that from 100 to 200 mg and the Cmax and AUC0−inf increased with dose but the ratio of increase was greater than the dose ratio [5].


Study DE766-A-J201 /08-TH-8201: The mean (SD) for Cmax was 224.33 (85.31) µg/mL, the AUC0-168hwas 16393.88 (6840.66) μg·h/mL, AUC0-infwas 20370.07 (9388.47) μg·h/mL, CLwas 30.22 (30.93) mL/h, the VD was2.27 (1.28) L, the MRT was 93.30 (25.05) h and t1/2was 65.91 (18.63) h.
The TheraCIM pharmacokinetic parameters in this study were generally similar to those in the previous TheraCIM phase I study in Japanese patients with solid tumors (DE766-A-J101). The pharmacokinetic profiles of irinotecan hydrochloride and SN-38 in combination with TheraCIM were consistent with that observed with irinotecan monotherapy [6].

Study HH-2004/2: Pharmacokinetic of TheraCIM monotherapy and in combination with 1000 mg/m2 gemcitabine was assessed in this study.Increasing the dose from 200 mg to 400 mg TheraCIM led to a statistically significant increase for PK parameter AUC, Cmax and measured Trough Values.Terminal half life increased significantly to dose 800 mg. There was no effect of thetested co-medication with gemcitabine on the calculated PK parameter of the 400 mg dose of TheraCIM.


TheraCIM pharmacodynamics activity is thought to occur via binding to EGFR, which prevents stimulation of the receptor by endogenous ligands, resulting in the loss of EGF activity.
Two studies were performed to evaluate the pharmacodynamics (PD) of TheraCIM: Study IIC RD EC-076 and Study DE766-A-J201/08-TH-8201 [6,7].

Study IIC RD EC-076: In all studied SCCHN patients, EGFR was detectedin tumor cells. p-EGFR was detected in tumor cellsmainly at undifferentiated areas and within the infiltrating edge. p-ERK1/2 and Ki-67 expression were also mainlylocated in the infiltrating borders of the tumors, whereasp-AKT was diffusely present. Total ERK1/2 and AKT werebroadly expressed in tumor cells.

The pharmacodynamic effects in paired tumor samplesshowed that

  • TheraCIM induced a modest butsignificant downregulation of p-EGFR
    (H-score: 243 ±16.34 in pre-therapy versus 180 ± 7.5 in on-therapy specimens, P = 0.034)
  •  TheraCIM reducedtumor cell proliferation
    (H-score: 195 ± 43 in pre-therapyversus 150 ± 42.2 in on-therapy, P = 0.012) and showed atrend for p-ERK1/2 (H-score: 129 ± 32.9 in pre-therapy versus103 ± 19.2 in on-therapy, P = 0.091).
  •  TheraCIM significantly upregulated p-AKT expression
    (H-score: 105 ±37.8 in pre-therapy versus 140 ± 55.6 in on-therapy, P =0.043), suggesting feedback mechanisms on AKT in the presenceof EGFR inhibitors.
    Expression levels of total proteins(EGFR, ERK1/2, and AKT) were not different both in skinand tumor samples. No significant difference in the effectswas observed between the two TheraCIM dose groups [7].
  •  The mAb inhibited the phosphorylation of EGFR in the skin and reduced the expression of the nuclear proliferation marker Ki67 and the characteristic perivascular lymphocytic inflammatory infiltrate observed with other EGFR inhibitors was not observed on the superficial dermis of the patients in this study.
  •  The mAb TheraCIM inhibited the activation of the EGFR and of the ERK (MAPK) protein in the tumour. An increase in the phosphorylated pAKt protein was also observed as well as a decrease in the proliferation rate measured by the ki67 marker.
  • The pharmacodynamic evaluation showed that the monoclonal antibody caused inhibition of the phosphorylation in the skin and in the tumor (Wilcoxon test, p=0.042 skin, p=0.034 tumor). The tendency in the decrease of the pERK (p=0.091) and a significant decrease in the ki67 marker (p=0.043) suggests inhibition of other markers in the signaling chain of the EGFR in the tumor. A significant increase in the expression of the p-Akt in the tumor (p=0.043) and not in the skin was observed as previously described for other EGFR inhibitors.
  •  No inflammatory lymphocytic infiltrate or perifoliculitis in the skin was observed as it has occurred for other EGFR antagonists. No relationship between the antibody dose given (200 or 400 mg) and the pharmacodynamic effects was observed.

It can be concluded that after a single exposure, the monoclonal antibody inhibited the phosphorylation of the EGFR. A tendency in the decrease of the activation of other distal markers in the signaling cascade was observed, which is compatible with the expected biological effect. The absence of inflammatory infiltrate in the skin could explain the non-toxic effect of nimotuzumab on the skin [7].


Study DE766-A-J201 / 08-TH-8201: In this study the EGFR protein expression levels, EGFR gene amplification levels, K-RAS gene mutations, and HER2 protein expression levels were measured using tumor tissue specimens from 48 patients who had given informed consent for biomarker analysis.

  •  EGFR protein expression levels in tumor tissues measured by IHCin the assessable tumor tissues of 47 patients (57.3 % of the full analysis set population) (21 in Arm A and 26 in Arm B) was detected to be positive tumors (≥ 1+) in 26 patients (11 in Arm A (52.4 %), 15 in Arm B (57.7 %)).
  •  EGFR gene amplification levels in tumor tissues measured by FISH in the specimens of 46 patients (56.1% in the full analysis set) (20 in Arm A and 26 in Arm B) were detected to had gene amplification or high polysomy in 10 patients (4 inArm A (20 %), 6 in Arm B (23.07 %)).
  •  K-RAS gene mutations measured using genomic DNA from tumor tissues in the specimens of 48 patients (58.5% in the full analysis set) (22 in Arm A and 26 in Arm B) was detected in 2 patients in Arm B (7.7 %) and 46 patients (22 in Arm A (100 %) and 24 in Arm B (92.3 %)) had wild-type K-RAS.
  •  HER2 protein expression levels in tumor tissues measured by IHC in the specimens of 47 patients (57.3% in the full analysis set) (21 in Arm A and 26 in Arm B) were detected (HER2-positive tumors (≥ 2+)) in 6 patients (3 in Arm A (14.3 %), 3 in Arm B (11.5 %)).

In this study as second line on gastric tumors, a subset analysis showed a median PFS of 118.5 days in the EGFR 2+/3+ subgroup of the nimotuzumab-irinotecan group and 59.0 days in the corresponding subgroup of the irinotecan group and the response rate was 33.3 % and 0.0 %, respectively, showing that tumor cells overexpressing EGFR are common, and allow selective binding of nimotuzumab to be effective on these tumors [6]


Comparison of PK/PD parameters across the studies.

Intravenous infusions of TheraCIM using drug substance and drug product manufactured using hollow fiber and stirred tank fermentation processes exhibited non-linear PK at weekly doses ranging from 50 mg to 800 mg. TheraCIM clearance decreased with increasing doses to 400 mg then appeared to make a plateau [3, 4].


Targeted antibody like TheraCIM disappear from the central compartment via, a specific, saturable target (antigen), which is the EGFR, a specific elimination process based on receptor/ligand internalization. At a certain plasma concentration, EGFR will become saturated. At this point, second, non-saturable, unspecific elimination becomes apparent, as indicated that after a certain administered dose (400 mg) CL and t1/2 values remain constant [4].

No metabolism or mass-balance studies have been performed and it is our understanding that this can be acceptable since biotechnology-derived pharmaceuticals are expected to degrade into small peptides and individual amino acids [1].


The pharmacodynamics data on patients with squamous cell carcinoma of the head and neck indicate the TheraCIM at doses within target dose-range led to down regulation of EGFR in tumor tissues and confirmed the ability of TheraCIM to decrease EGFR phosphorylation. Downstream effects were observed in tumor cells but not in skin, a finding that may help to explain the lack of skin rash in patients treated with TheraCIM [7].


In study DE766-A-J201 /08-TH-8201, skin rash occurred in ten patients (25.0 %) in the nimotuzumab-irinotecan group, which represents a lower frequency than that reported for patients receiving other anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab [8, 9]. Furthermore, there were no cases of severe (Grade 3) skin toxicity in either treatment group.The frequency and severity of skin toxicity associated with TheraCIM appears to be lower than that associated with other anti-EGFR antibodies. The safety profile of TheraCIM could be expected to maintain good quality of life as well as compliance and shows potential for combination of TheraCIM with irinotecan.


The mechanism underlying this lower frequency of skin toxicity of TheraCIM compared with that of other known anti-EGFR antibodies has been investigated in several recent studies [3, 7, 10]. These studies suggested that a low incidence of skin toxicity may be associated with the following: (i) the intermediate affinity (KD = 4.3 x 10-9 M) of TheraCIM, which is at least one order of magnitude lower than that of cetuximab and two order lower than that of panitumumab; and (ii) the different binding profile of TheraCIM, which requires bivalent binding for stable attachment to the cellular surface compared with that of cetuximab, which requires only monovalent binding [11]. This finding implies that TheraCIM binding to EGFR occurs only when the surface EGFR density on the cells is sufficiently from moderate expression to high expression that will allow bivalent binding.


  • ICH Topic S6 – Step 4 Note for guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals (CPMP/ICH/302/95), 1997.
  • Harding J, Burtness B: Cetuximab: An epidermal growth factor receptor chimeric human-murine monoclonal antibody. Drugs of Today (2005) 41(2):107-127.
  • Crombet T, Osorio M, Cruz T, Roca C, del Castillo R, Mon R, Iznaga-Escobar N, Figueredo R, Koropatnick J, Renginfo E, Fernandez E, Alvarez D, Torres O, Ramos M, Leonard I, Perez R, Lage A. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J ClinOncol 2004, 22: 1646-1654.
  • Crombet T, Torres L, Neninger E, Catala M, Solano ME, Perera A, Torres O, Iznaga-EscobarN, Torres F, Perez R and Lage A. Pharmacological Evaluation of Humanized Anti-Epidermal Growth Factor Receptor, Monoclonal Antibody h-R3, in Patients With Advanced Epithelial-Derived Cancer. J Immunother. 2003, Mar-Apr;26(2):139-148
  • Okamoto W, Yoshino T, Takahashi T, Okamoto I, Ueda S, Tsuya A, Boku N, Nishio K, Fukuoka M, Yamamoto N, Nakagawa K. A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. Cancer ChemotherPharmacol. 2013 Nov;72(5):1063-1071.
  • Satoh T., Hee Lee K., Young Rha S., Sasaki Y., Hoon Park S., Komatsu Y., Yasui H., You Kim T., Yamaguchi K., Fuse N., Yamada Y., Ura T., Kim SY., Munakata M., Saitoh S., Nishio K.. Morita S., Yamamoto E., Zhang Q., Kim JM., Kim YH., Sakata Y. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer 2015, 18(4):824-832.
  • Rojo F, Gracias E, Villena N, Cruz T, Corominas JM, Corradino I, Cedeño M, Campas C, Osorio M, Iznaga N, Bellosillo B, Rovira A, Marsoni S, Gascon P, Serrano S, Sessa C, Crombet T, Albanell J. Pharmacodynamic trial of nimotuzumab in unresectable squamous cell carcinoma of the head and neck: a SENDO Foundation study.Clin Cancer Res. 2010 Apr 15;16(8):2474-2482.
  • Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490–499.
  • Waddell TS, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):481–489.
  • Crombet Ramos T., Rak J., Perez R., and Viloria-Pettit A. Antiproliferative, antiangiogenic and proapoptotic of h-R3: a humanized anti-EGFR antibody. Int J of Cancer 2002, 101:567-575.
  • Garrido G., Tikhomirov IA, Rabasa A., Yang E., Gracia E., Iznaga Escobar N., Fernandez LE, Crombet T, Kerbel RS, and Perez R. Bivalent binding by intermediate affinity of nimotuzumab. A contribution to explain antibody clinical profile. Cancer Biology & Therapy 2011, 11:4, pp. 373-382