Table 2.
Product name/Brand name | Antibody format | Target antigen | Antibody phage display type | Phage display technology | Clinical domain | Indication(s) | Highest development phase | Sponsor company |
---|---|---|---|---|---|---|---|---|
Adalimumab (D2E7)/Humira® | IgG1-κ | TNFAα | Humanization by Phage display guided selection using a naïve scFv-phage library (180) | CAT (51, 173–175) | Immunology, and inflammation (181–184) | RA | Approved 2002 | AbbVie |
PSA | Approved 2005 | |||||||
AS | Approved 2006 | |||||||
CD | Approved 2007 | |||||||
Psoriasis, severe chronic plaque | Approved 2008 | |||||||
JIA | Approved 2008 | |||||||
UC | Approved 2012 | |||||||
HS | Approved 2015 | |||||||
Fingernail psoriasis | Approved 2017 | |||||||
Ophthalmology (185) | Uveitis | Approved 2016 | ||||||
Adecatumumab (MT201) | IgG1 | EpCAM | Guided selection of light chain, naïve (IgD), Fab (186) | Micromet AG | Oncology (187–190) | Breast cancer, prostate cancer, colorectal cancer | Phase II | Amgen |
1D09C3 | IgG4 | HLA-DR | Synthetic scFv (191) | Morphosys's HuCAL® (177) | Oncology (192, 193) | HL, myeloma | Phase I | GPC Biotech AG |
Anetumab ravtansine (unconjugated BAY 86-1903, conjugate BAY 94-9343) | IgG1-λ conjugated to the maytansinoid tubulin inhibitor DM4 | MSLN | Synthetic Fab (194) | Morphosys's HuCAL GOLD® (178) | Oncology (195, 196) | Mesothelioma, mesothelin-expressing ovarian cancer, non-small cell lung cancer and pancreatic cancer | Phase II | Bayer |
Amatuximab (MORAb-009) | IgG1-κ | MSLN | Immune scFv (197, 198) | NCI, US | Oncology (199, 200) | Mesothelioma, mesothelin-expressing pancreatic cancer | Phase II | Eisai Inc |
Atezolizumab (MPDL3280A)/Tecentriq™ | IgG1-κ | PD-L1 | Antibody phage display library (201, 202) | Genentech | Oncology (203–208) | Renal cancer | Phase I | Roche |
Solid tumors | Phase II | |||||||
SCLC | Phase III | |||||||
Malignant melanoma | Phase III | |||||||
Mesothelioma (PMID: 32206576) | Phase III | |||||||
Bladder cancer | Phase III | |||||||
RCC | Phase III | |||||||
HCC | Phase III | |||||||
NSCLC | Approved 2016 | |||||||
Urothelial Carcinoma | Approved 2016 | |||||||
Urothelial bladder cancer | Approved 2017 | |||||||
Breast cancer | Approved 2019 | |||||||
Avelumab/Bavencio® | IgG1-λ | PD-L1 | Naïve Fab (209) | Dyax (176) | Oncology (210–216) | Ovarian cancer | Phase III | Merck Serono/Pfizer |
Gastric cancer | Phase III | |||||||
NSCLC | Phase III | |||||||
Solid tumors | Phase I | |||||||
mMCC, metastatic urothelial carcinoma | Approved 2017 | |||||||
RCC | Approved 2019 | |||||||
Belimumab (LymphoStat-B)/Benlysta® | IgG1-λ | BLyS | Naïve scFv (217) | CAT | Immunology, and inflammation (218–220) | SLE | Approved 2011 | GSK/HGSI |
Vasculitis | Phase III | |||||||
Bertilimumab (CAT-213) | IgG4-κ | CCL11, eotaxin-1 | Naïve scFv (221) | CAT | Immunology (222–225) | Severe ocular allergies | Phase I | Immune Pharmaceuticals |
CD | Phase II | |||||||
UC | Phase II | |||||||
Bullous pemphigoid | Phase II | |||||||
Bimagrumab (BYM338) | IgG1-λ | ActRII | Synthetic human Fab (226) | Morphosys's HuCAL GOLD® | Endocrinology, and Immunology (227) | Type 2 diabetes | Phase II | Novartis |
Immunology, and myology (228–231) | Cachexia | Phase II | ||||||
Sporadic inclusion body myositis | Phase III | |||||||
Musculoskeletal diseases | Phase II | |||||||
Sarcopenia | Phase II | |||||||
Carlumab (CNTO 888) | IgG1-κ | CCL2/MCP-1 | Synthetic Fab (232) | Morphosys's HuCAL GOLD® | Oncology (233, 234) | Solid tumors | Phase I | Janssen |
Oncology (235) | Prostate cancer | Phase II | ||||||
Pulmonary, and Respiratory diseases (236) | Pulmonary fibrosis | Phase II | ||||||
Cixutumumab (IMC-A12) | IgG1-λ | IGF1R | Naïve Fab (237) | Dyax | Oncology (238–240) | NSCLC, HCC, solid tumors | Phase II | Eli Lilly/ImClone |
Foravirumab (CR4098) | IgG1-κ | Rabies virus glycoprotein | Immune scFv (241, 242) | Crucell | Immunology, and Infectiology (5) | Prophylaxis of rabies | Phase III | Sanofi |
Fresolimumab (GC-1008) | IgG4-κ | TGFβ | Naïve scFv (243) | CAT | Oncology, and immunology (244–247) | Scleroderma, metastatic breast cancer, NSCLC, fibrosis, focal segmental glomerulosclerosis | Phase II | Genzyme/Sanofi |
Ixekizumab (LY2439821)/Taltz® | IgG4-κ | IL17A | Immune Fab (248) | Eli Lilly | Immunology (249–252) | RA | Phase II | Eli Lilly |
Psoriasis | Approved 2016 | |||||||
PSA | Approved 2017 | |||||||
AS | Approved 2019 | |||||||
Mapatumumab (HGS-ETR1) | IgG1-λ | TRAIL-1 | Naïve scFv (253) | CAT | Oncology (254–257) | Multiple myeloma, colorectal cancer, NSCLC, NHL, cervical cancer | Phase II | GSK/HGSI |
Mavrilimumab (CAM-3001) | IgG4-λ2 | GM-CSFRα | Naïve scFv (258) | CAT | Immunology (259–261) | RA, GCA, COVID-19 | Phase II | MedImmune /AstraZeneca |
Moxetumomab pasudotox (CAT-8015)/Lumoxiti™ | Murine IgG1 dsFv and a Pseudomonas exotoxin A | CD22 | Affinity maturation of BL22 by phage display (122, 262) | CAT | Oncology (263, 264) | HCL | Approved 2018 | MedImmune /AstraZeneca |
Namilumab (MT203) | IgG1-κ | GM-CSF | Humanization rat scFv by Phage display guided selection using a naïve human scFV-phage library (human VH contains rat CDR3) (265, 266) | Micromet AG/CAT | Immunology (267–269) | RA, AS, psoriasis | Phase II | Takeda |
Necitumumab (IMC-11F8)/Portrazza™ | IgG1-κ | EGFR | Naïve Fab (270, 271) | Dyax | Oncology (272–275) | NSCLC | Approved 2015 | Eli Lilly/AstraZeneca |
Colorectal cancer | Phase II | |||||||
Solid tumors | Phase I | |||||||
Opicinumab (BIIB-033, Li81) | IgG1-κ | LINGO 1 | Naïve Fab (276) | Dyax | Immunology, and inflammation (277, 278) | MS, and Optic neuritis | Phase II | Biogen |
Tanibirumab (Olinvacimab, TTAC-0001) | IgG1-κ-λ | VEGFR2 | Naïve scFv (279, 280) | PharmAbcine | Oncology (281, 282) | Solid tumors | Phase I | PharmAbcine |
Glioblastoma | Phase II | |||||||
Utomilumab (PF-05082566) | IgG2-λ | 4-1BB (CD137) | Synthetic Fab (283) | Morphosys's HuCAL GOLD® | Oncology (284–288) | Solid tumors | Phase I | Pfizer |
Breast cancer, B-cell lymphoma, NHL | Phase II | |||||||
Ganitumab (AMG 479) | IgG1-κ | IGF-1R | Naïve Fab (289, 290) | Dyax | Oncology (291–293) | Metastatic colorectal cancer | Phase II | Amgen |
Pancreatic cancer, metastatic Ewing Sarcoma | Phase III | |||||||
AMG 780 | IgG2 | Ang-1 and−2 | Naïve Fab (294) | Dyax | Oncology (295) | Solid tumors | Phase I | Amgen |
Caplacizumab (ALX-0081)/Cablivi™ | Humanized VH-VH. Genetically linked by a triple-alanine linker | VWF A1 domain | Immune, camelidae-derived nanobody library (296–298) | Nanobody® | Cardiology, and hematology (299, 300) | aTTP | Approve 2018 | Sanofi/Ablynx |
Ramucirumab (IMC1121B)/Cyramza® | IgG1-κ | VEGFR2 | Naïve Fab (301, 302) | Dyax | Oncology (303–310) | Tumors vasculature | Phase I | Eli Lilly |
Solid tumors | Phase II | |||||||
Breast cancer, Bladder cancer | Phase III | |||||||
Gastric cancer, NSCLC | Approved 2014 | |||||||
Colorectal cancer | Approved 2015 | |||||||
HCC | Approved 2019 | |||||||
Ranibizumab (Fab-12 variant Y0317)/Lucentis® | Fab-IgG1-κ | VEGFA | Affinity maturation of bevacizumab (311, 312) by phage display (313) | Genentech | Immunology, and Ophthalmology (314–319) | nAMD | Approved 2006 | Roche/Novartis |
MEfRVO | Approved 2010 | |||||||
DME | Approved 2012 | |||||||
CNV | Approved 2016 | |||||||
Diabetic retinopathy | Approved 2017 | |||||||
MOR202 | IgG1-λ | CD38 | Synthetic human Fab (320) | Morphosys's HuCAL GOLD® | Oncology (321) | MM | Phase II | Morphosys/I-MAB Biopharma |
Darleukin (bifikafusp alfa, L19-IL2) | L19 scFv-IL2 fusion, diabody | EDB-FN | Semi-synthetic scFv (322) | Alessandro Pini's library (168, 322) | Oncology (323, 324) | Solid cancers | Phase I/II | Philogen |
Metastatic melanoma | Phase III | |||||||
Fibromun (Onfekafusp alfa, L19-TNF) | L19 scFv-TNFα fusion, diabody | EDB-FN | Semi-synthetic scFv (325) | Alessandro Pini‘s library | Oncology (324, 326, 327) | Glioma | Phase II | Philogen |
Metastatic Melanoma, Soft tissue sarcoma, glioma | Phase III | |||||||
Radretumab (131I-labeled L19SIP) | [L19 scFv-IgE-CH4-Iodine-131 fusion]2 | EDB-FN | Semi-synthetic scFv (328) | Alessandro Pini's library | Oncology (329, 330) | Solid tumors, lymphomas | Phase II | Philogen |
Raxibacumab/ABthrax® | IgG1-λ | Anthrax PA, Bacillus anthracis | Naïve scFv (331) | CAT | Infectious diseases (332) | Inhalation anthrax | Approved 2012 | GSK/HGSI |
Otilimab (MOR04357, GSK3196165) | IgG1-λ | GM-CSF | Synthetic Fab (333) | Morphosys's HuCAL GOLD® | Immunology (260, 334, 335) | OS | Phase II | GSK |
RA | Phase III | |||||||
Seribantumab (MM-121) | IgG2-λ | HER3 | Naïve Fab (336, 337) | Dyax | Oncology (248, 338, 339) | Ovarian cancer, breast cancer, NSCLC | Phase II | Sanofi/Merrimack |
Tralokinumab (CAT-354, BAK 1.1) | IgG4-λ | IL13 | Naïve scFv (340, 341) | CAT | Immunology (342, 343) | Asthma, atopic dermatitis | Phase III | MedImmune /AstraZeneca/LEO pharma |
Ianalumab (VAY736, B-1239) | Defucosylated IgG1-κ | BAFF-R | Synthetic Fab (344, 345) | Morphosys's HuCAL GOLD®/ POTELLIGENT® technology |
Immunology (346–348) | CLL | Phase I | Novartis |
pSS, MS | Phase III | |||||||
Teleukin (F16-IL2) | F16 scFv-IL2 fusion, diabody | A1 domain of tenascin-C | Synthetic scFv (349, 350) | ETH-2 library (351) | Oncology (352–354) | AML | Phase I | Philogen |
MCC, breast cancer | Phase II | |||||||
Xentuzumab (BI 836845) | IgG1-λ | IGF-I, IGF-II | Synthetic Fab (355) | Morphosys's HuCAL GOLD® | Oncology (356–359) | NSCLC, solid tumors | Phase I | Boehringer Ingelheim |
Breast cancer | Phase II | |||||||
Setrusumab (BPS-804, MOR05813) | IgG2-λ | SOST | Synthetic Fab (178, 360) | Morphosys's HuCAL GOLD® | Supportive therapy (361–363) | OI, HPP, post-menopausal women with low BMD | Phase II | Mereo BioPharma/Novartis |
IMC-3C5 (hF4–3C5, LY3022856) | IgG1 | VEGFR-3 | Naïve Fab (364) | Dyax | Oncology (365) | Solid tumors | Phase I | Eli Lilly/ImClone |
Aprutumab (BAY 1179470) | IgG1-λ | FGFR2 | Semisynthetic scFv (366) | BioInvent's n-CoDeR™ library (367) | Oncology (368) | Solid tumors | Phase I | Bayer HealthCare |
BAY 1093884 | IgG2 | TFPI | Synthetic Fab (369–371) | Morphosys's HuCAL GOLD® | Hematology (372) | Hemophilia A and B | Phase II | Bayer HealthCare |
BAY 1213790 | IgG1 | FXI | Naïve Fab (373, 374) | Dyax | Hematology (375) | VTE | Phase II | Bayer HealthCare/XOMA |
CNTO-6785 | IgG1-λ | IL17A | Synthetic Fab (376) | Morphosys's HuCAL GOLD® | Immunology (377, 378) | COPD, RA | Phase II | Janssen |
CNTO-3157 | IgG4-κ | TLR-3 | Synthetic Fab (379) | Morphosys's HuCAL GOLD® | Immunology (380) | Asthma | Phase I | Janssen |
Briakinumab (ABT-874) | IgG1-λ | IL12 and IL23 | Naïve scFv (381, 382) | CAT | Immunology (383, 384) | MS | Phase II | Abbott |
Psoriasis | Phase III | |||||||
BHQ880 | IgG1-λ | DKK1 | Synthetic Fab (385) | Morphosys's HuCAL GOLD® | Oncology (386, 387) | MM | Phase II | Novartis |
BI-1206 (6G11) | IgG1 | FcγRIIB (CD32B) | Semisynthetic scFv (388) | BioInvent's n-CoDeR™ library | Oncology (389) | NHL, CLL | Phase I/II | BioInvent |
Dekavil (F8-IL10) | F8 scFv-Interleukin 2 (IL2) fusion, diabody | EDA-FN | Synthetic scFv (390) | ETH-2 library | Immunology (391) | RA | Phase II | Philogen/Pfizer |
Gancotamab (MM-302, C6.5) | scFv-λ targeted liposomal doxorubicin | HER2 | Naïve scFv (392, 393) | CAT | Oncology (394, 395) | Breast cancer | Phase II | Merrimack |
Guselkumab (CNTO1959)/Tremfya™ | IgG1-λ | IL23, subunit P19 | Synthetic Fab (396, 397) | Morphosys's HuCAL GOLD® | Immunology (398–400) | RA, palmoplantar pustulosis | Phase III | Janssen |
Psoriasis | Approved 2017 | |||||||
Lupartumab amadotin (BAY 1129980) | Antibody-drug conjugate (ADC), IgG1-λ conjugated with auristatin W derivative | LYPD3 (C4.4A) | Semisynthetic scFv (401) | BioInvent's n-CoDeR™ library | Oncology (401) | Solid tumors | Phase I | Bayer |
Lanadelumab (DX-2930)/Takhzyro® | IgG1-κ | pKal | Naïve Fab (402) | Dyax | Immunology (403, 404) | HAE | Approved 2018 | |
Lexatumumab (HGS-ETR2) | IgG1-λ | TRAIL-R2 (DR5) | Naïve scFv (79, 253) | CAT | Oncology (405, 406) | Solid tumors | Phase I | HGS |
Oleclumab (MEDI9447) | IgG1-λ | CD73 | Naïve scFv (407) | CAT | Oncology (408–410) | Solid tumors | Phase I | AstraZeneca /MedImmune |
NSCLC, breast cancer | Phase II | |||||||
Tarextumab (OMP-59R5) | IgG2-κ | Notch2/3 | Synthetic Fab (411) | Morphosys's HuCAL GOLD® | Oncology (412–415) | Solid tumors | Phase I | GSK/OncoMed |
Pancreatic Cancer, SCLC | Phase II | |||||||
Elgemtumab (LJM716) | IgG1-mk | HER3 | Synthetic Fab (416, 417) | Morphosys's HuCAL GOLD® | Oncology (418–421) | Breast cancer, gastric cancer | Phase I | Novartis |
Esophageal cancer, HNSCC | Phase I/II | |||||||
Gantenerumab (R1450) | IgG1-κ | Amyloid-β (Aβ) | Synthetic Fab (422) | Morphosys's HuCAL®-Fab1 library (170) | Neurology (423) | Alzheimer's disease | Phase III | Roche |
Vantictumab (OMP-18R5) | IgG2-λ | FZD family receptor, including FZD1, FZD2, FZD5, FZD7, and FZD8 | Synthetic Fab (424) | Morphosys's HuCAL GOLD® | Oncology (425, 426) | Breast cancer; NSCLC, pancreatic cancer | Phase I | OncoMed/Bayer |
MEDI4212 | IgG1-λ | IgE | Naïve scFv (427) | CAT | Immunology (428) | Asthma | Phase I | MedImmune/ AstraZeneca |
Drozitumab (Apomab, PRO95780) | IgG1-λ | TRAIL-R2 (DR5) | scFv (429) | Genentech | Oncology (430–432) | Solid tumors | Phase I | Genentech |
NHL, NSCLC | Phase II | |||||||
Tesidolumab (LFG316) | IgG1-λ | Complement 5 (C5) | Synthetic Fab (433) | Morphosys's HuCAL GOLD® | Inflammation, and Ophthalmology (434, 435) | Geographic Atrophy, uveitis, panuveitis, PNH, AMD | Phase II | Novartis |
Emapalumab (NI-0501)/Gamifant® | IgG1-λ | Interferon-gamma | Naïve scFv (436) | CAT | Hematology (437) | HLH | Approved 2018 | NovImmune SA |
Imalumab (Anti-MIF, BAX69) | IgG1-κ | MIF | Naïve Fab (438) | Dyax | Oncology (439, 440) | Colorectal cancer, malignant ascites, ovarian cancer | Phase II | Baxter/Takeda |
Bersanlimab (BI-505) | IgG1-λ | ICAM1 | Semisynthetic scFv (441) | BioInvent's n-CoDeR™ library | Oncology (442) | MM | Phase II | BioInvent |
Orticumab (BI-204/MLDL1278A) | IgG1-λ | oxLDL | Semisynthetic scFv (443) | BioInvent's n-CoDeR™ library | Cardiology (441) | Atherosclerosis | Phase II | BioInvent/ Genentech |
PC-mAb (M99-B05) | IgG1-κ | ChoP | Naïve human Fab (444, 445) | Dyax | Cardiology (446) | Myocardial infarction | Phase II | Athera Biotechnologies/ Dyax |
m102.4 | IgG1-κ | Ephrin-B2 and -B3 receptor binding domain of the henipavirus G envelope glycoprotein | Affinity maturation of clone m102 by phage display (447, 448) | NCI | Infectious diseases (449) | NiV and HeV infections | Phase I | Profectus Biosciences |
Cusatuzumab (ARGX-110) | Defucosylated IgG1-λ | CD70 | Immunized lama Fab-based library followed by antibody humanization using synthetic libraries with phage expressing germlined Fabs (450–452) | SIMPLE Antibody™/ POTELLIGENT® technology |
Oncology (453, 454) | AML | Phase II | Argenx/Janssen |
Solid tumors and hematologic malignancies | Phase I | |||||||
ARGX-111 | Defucosylated IgG1-λ | c-MET | Immunized lama Fab-based libraries followed by antibody humanization by re-assembling into human IgG1 and λ light chain constant domains (455–457) | SIMPLE Antibody™/ POTELLIGENT® technology/NHance™ technology |
Oncology (458) | Solid tumors | Phase I | Argenx |
Data current as of May 20, 2020.
TNFAα, Tumor necrosis factor-alpha; RA, Rheumatoid arthritis; PSA, Psoriatic arthritis; AS, Ankylosing spondylitis; CD, Crohn's disease; JIA, Juvenile Idiopathic Arthritis; UC, Ulcerative colitis; HS, Hidradenitis suppurativa; EpCAM, Epithelial cell adhesion molecule; HLA-DR, Human Leukocyte Antigen–DR isotype; HL, Hodgkin's lymphoma; HLA-DR, Human Leukocyte Antigen–DR isotype; MSLN, Mesothelin; NCI, The National Cancer Institute; PD-L1, Programmed cell death-ligand 1; NSCLC, Non-small cell lung cancer; SCLC, Small cell lung cancers; RCC, Renal cell carcinoma; HCC, Hepatocellular carcinoma; mMCC, metastatic Merkel cell carcinoma; BLyS, B-lymphocyte stimulator; SLE, Systemic Lupus Erythematosus; CCL11, CC chemokine ligand 11; ActRII, Myostatin/activin type II receptor; CCL2, CC chemokine ligand 2; MCP-1, Monocyte chemoattractant protein 1; IGF1R, Insulin-like growth factor 1 receptor; TGFβ, Transforming growth factor β; IL17A, Interleukin-17A; TRAIL-1, TNF-related apoptosis- inducing ligand receptor 1; NHL, Non-Hodgkin's lymphoma; GM-CSFRα, Granulocyte macrophage-colony stimulating factor receptor alpha; GCA, Giant cell arteritis; COVID-19, novel coronavirus 2019; HCL, Hairy cell leukemia; GM-CSF, Granulocyte macrophage-colony stimulating factor receptor; EGFR, Epidermal Growth Factor Receptor; LINGO-1, Leucine-rich repeat and Ig containing Nogo receptor interacting protein-1; MS, Multiple sclerosis; VEGFR2, Vascular endothelial growth factor receptor 2; Ang-1 and−2, Angiopoietin 1 and 2; VWF, von Willebrand factor; aTTP, Acquired thrombotic thrombocytopenic purpure; VEGFR2, Vascular endothelial growth factor-receptor 2; VEGFA, Vascular endothelial growth factor A; nAMD, Neovascular age-related macular degeneration; MEfRVO, Macular edema following Retinal Vein Occlusion; DME, Diabetic macular edema; CNV, Visual impairment due to choroidal neovascularisation; MM, Multiple myeloma; EDB-FN, Extradomain-B of fibronectin; IL2, Interleukin 2; PA, Protective antigen; OS, Osteoarthritis; HER3, Human epidermal growth factor receptor 3; BAFF-R, B-cell-activating factor receptor; CLL, Chronic lymphocytic leukemia; ETH, Swiss Federal Institute of Technology Zürich; pSS, Primary Sjögren's syndrome; AML, Acute myeloid leukemia; IGF-II, Insulin-like growth factor II; SOST, Sclerostin; OI, Osteogenesis imperfecta; HPP, Hypophosphatasia; BMD, Bone mineral density; VEGFR-3, Vascular endothelial growth factor receptor-3; FGFR2, Fibroblast growth factor receptor 2; TFPI, Tissue factor pathway inhibitor; FXI, Coagulation factor XI; VTE, Venous thromboembolism; COPD, Chronic obstructive pulmonary disease; TLR-3, Toll-Like Receptor 3; DKK1, Dickkopf 1; EDA-FN, Extra-domain A of fibronectin; HER2, Human epidermal growth factor receptor 2; LYPD3, Ly6/PLAUR domain-containing protein 3; pKal, Plasma kallikrein; HAE, Hereditary Angioedema, TRAIL-R2, TRAIL receptor 2; DR5, death receptor 5; SCLC, Small cell lung cancer; HER3, Human epidermal growth factor receptor 3; HNSCC, Head and neck squamous cell carcinoma; Aβ, Amyloid-β; FZD, Frizzled receptor; PNH, Paroxysmal nocturnal haemoglobinuria; AMD, Age-related macular degeneration; HLH, Hemophagocytic lymphohistiocytosis; MIF, Macrophage migration inhibitory factor; ICAM1, Intercellular adhesion molecule 1; oxLDL, Oxidized low-density lipoprotein; ChoP, Phosphorylcholine; MI, Myocardial infarction; NiV, Nipah virus; HeV, Hendra virus; HGFR, Hepatocyte growth factor receptor.