Ofatumumab

Ofatumumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	CD20
Clinical data
Trade names	Arzerra
AHFS/Drugs.com	Monograph
MedlinePlus	a610009
License data	EU EMA: by INN US FDA: Ofatumumab
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	IV
ATC code	L01XC10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Biological half-life	14 days
Identifiers
CAS Number	679818-59-8^N
DrugBank	DB06650^N
ChemSpider	none
UNII	M95KG522R0
ChEMBL	CHEMBL1201836^N
Chemical and physical data
Formula	C₆₄₈₀H₁₀₀₂₂N₁₇₄₂O₂₀₂₀S₄₄
Molar mass	146.1 kg/mol
^NY (what is this?) (verify)

Ofatumumab^[1] (trade name Arzerra, also known as HuMax-CD20) is a fully human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is FDA approved for treating chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in treating follicular lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Ofatumumab has also received conditional approval in Europe for the treatment of refractory chronic lymphocytic leukemia. This makes ofatumumab the first marketing application for an antibody produced by Genmab, as well as the first human monoclonal antibody which targets the CD20 molecule that will be available for patients with refractory CLL.

Medical uses

Its only indication that has received regulatory approval is chronic lymphocytic leukemia (CLL).^[2]^[3]^[4]

FDA Approval

It first received FDA approval on April 17, 2014, for use in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate^[2] MHRA approval on the 19th of April 2010,^[4]

EMA Approval

EMA approval on the 14th of June 2010^[3] and Health Canada approval on the 13th of August 2012.^[5]

Adverse effects

Adverse effects by frequency:^[2]^[3]^[4]
Very common (>10% frequency):

Lower respiratory tract infection, including pneumonia
Upper respiratory tract infection
Rash
Anemia
Neutropenia

Common (1-10% frequency):'

Sepsis
Herpes virus infection
Urinary tract infection
Febrile neutropenia
Leucopenia
Thrombocytopenia
Anaphylactoid reactions
Hypersensitivity
Tachycardia
Hypotension
Hypertension
Bronchospasm
Hypoxia
Dyspnoea (shortness of breath)
Chest discomfort
Pharyngolaryngeal pain
Cough
Nasal congestion
Small bowel obstruction
Diarrhoea
Nausea
Urticaria (hives)
Itchiness
Flushing
Back pain
Cytokine release syndrome
Pyrexia (fever)
Rigors
Chills
Hyperhidrosis
Fatigue

Uncommon (0.1-1% frequency):

Agranulocytosis
Coagulopathy
Red cell aplasia
Lymphopenia
Anaphylactic shock
Tumour lysis syndrome

Rare (<0.1% frequency):

Hepatitis B infection or reactivation

Ofatumumab has received a black box warning regarding the potential for it to cause progressive multifocal leukoencephalopathy and hepatitis B reactivation.^[6] Likewise it is also advised that doctors watch cautiously for small bowel obstruction, neutropenia, thrombocytopenia, infusion reactions or an increased risk for infection.^[6]

Contraindications

It is contraindicated in individuals that have hypersensitivity to ofatumumab or any of its excipients.^[4]

Interactions

No formal drug interaction studies have been conducted with ofatumumab.^[2] Although it is advised that patients are not administered live virus vaccines (e.g. the oral polio vaccine) while undergoing treatment with ofatumumab due to the compromised ability to fight the attenuated viruses seen in patients being treated with ofatumumab.^[6]

Mechanism

Ofatumumab is a humanised anti-CD20 monoclonal antibody whose epitope is distinct from that of rituximab.^[7] The CD20 antigen is expressed on solely B cell lymphocytes.^[7] Compared with rituximab, ofatumumab binds more tightly to CD20 with a slower off-rate.^[7] It causes cytotoxicity in the cells that express CD20 by means of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).^[7]

Clinical trials

Status of clinical trials of ofatumumab conducted by Genmab and GSK, as of late 2010.

Relapsed follicular non-Hodgkin's lymphoma (NHL)-Phase II^[8]
Rheumatoid arthritis (RA):
- Phase III – OFA110635/GEN410 – Ofatumumab in adult RA patients who have had an inadequate response to methotrexate^[9]
- Phase III – OFA110634/GEN411 – Ofatumumab in adult RA patients who have had an inadequate response to TNF-alphaantagonist therapy^[10]
Diffuse large B cell lymphoma (DLBCL) – Phase III^[11]
B-cell chronic lymphocytic leukemia (B-CLL) – Phase II^[12]
Waldenstrom's macroglobulinemia - Phase II^[13]
Relapsing remitting multiple sclerosis (RRMS)-Phase II^[14]
Mantle cell lymphoma (MCL)

References

↑ Zhang, Bodi (2009). "Ofatumumab". MAbs. 1 (4): 326–331. PMC 2726602 . PMID 20068404. doi:10.4161/mabs.1.4.8895.
1 2 3 4 "ARZERRA (ofatumumab) injection, solution [GlaxoSmithKline LLC]". DailyMed. GlaxoSmithKline LLC. September 2013. Retrieved 24 January 2014.
1 2 3 "Arzerra : EPAR - Product Information" (PDF). European Medicines Agency. Glaxo Group Ltd. 7 March 2013. Retrieved 24 January 2014.
1 2 3 4 "Arzerra (acetate formulation) -Summary of Product Characteristics (SPC)". electronic Medicines Compendium. GlaxoSmithKline UK. 27 November 2013. Retrieved 24 January 2014.
↑ "Product Information". Health Canada. GlaxoSmithKline Inc. 13 August 2012.
1 2 3 "Arzerra (ofatumumab) dosing, indications, interactions, and more". Medscape Reference. WebMD. Retrieved 24 January 2014.
1 2 3 4 Lin, TS (2010). "Ofatumumab: a novel monoclonal anti-CD20 antibody" (PDF). Pharmacogenomics and personalized medicine. 3: 51–59. PMC 3513208 . PMID 23226042.
↑ http://clinicaltrials.gov/ct2/show/NCT00394836?term=nct00394836&rank=1
↑ Clinical trial number NCT00611455 for "Investigating Clinical Efficacy of Ofatumumab in Adult RA Patients Who Had an Inadequate Response to MTX Therapy" at ClinicalTrials.gov
↑ Clinical trial number NCT00603525 for "Investigating Clinical Efficacy of Ofatumumab in Adult RA Patients Who Had an Inadequate Response to TNF-α Antagonist Therapy" at ClinicalTrials.gov
↑ Clinical trial number NCTNCT01014208 for "Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy Followed by Autologous Stem Cell Transplant in Relapsed or Refractory Diffuse Large B Cell Lymphoma (ORCHARRD" at ClinicalTrials.gov
↑ Clinical trial number NCT00349349 for "HuMax-CD20 in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Failing Fludarabine and Alemtuzumab" at ClinicalTrials.gov
↑ http://clinicaltrials.gov/ct2/show/NCT00811733?term=nct00811733&rank=1
↑ http://clinicaltrials.gov/ct2/show/NCT00640328?term=nct00640328&rank=1

Coiffier B, Lepretre S, Pedersen LM, et al. (February 2008). "Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study". Blood. 111 (3): 1094–100. PMID 18003886. doi:10.1182/blood-2007-09-111781.
Zhang B (July 2009). "Ofatumumab". MAbs. 1 (4): 326–31. PMC 2726602 . PMID 20068404. doi:10.4161/mabs.1.4.8895.
ClinicalTrials.gov: HuMax-CD20 search results

Targeted cancer therapy / antineoplastic agents (L01)

CI monoclonal antibodies ("-mab")

Receptor tyrosine kinase	ErbB: HER1/EGFR (Cetuximab Panitumumab) HER2/neu (Trastuzumab Trastuzumab emtansine)
Others for solid tumors	EpCAM (Catumaxomab Edrecolomab) VEGF-A (Bevacizumab)
Leukemia/lymphoma	lymphoid: CD20 (Ibritumomab Ofatumumab Rituximab Tositumomab), CD30 (Brentuximab), CD52 (Alemtuzumab) myeloid: CD33 (Gemtuzumab)

Tyrosine-kinase inhibitors ("-nib")

Receptor tyrosine kinase

RTK class III: C-kit and PDGFR (Axitinib
Masitinib
Pazopanib
Sunitinib
Sorafenib
Toceranib)
FLT3 (Lestaurtinib)

VEGFR
- Axitinib
- Cediranib
- Lenvatinib
- Nintedanib
- Pazopanib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Tivozanib
- Toceranib
- Vandetanib

RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK). c-MET inhibitor: Cabozantinib (also VEGFR2).

Non-receptor

bcr-abl
- Imatinib
- Dasatinib
- Nilotinib
- Ponatinib
- Radotinib

Src (Bosutinib
Dasatinib)

Janus kinase

MAP2K

EML4-ALK

Bruton's (Ibrutinib)

Other

fusion protein against VEGF (Aflibercept)
proapoptotic peptide against ANXA2 and prohibitin (Adipotide)
exotoxin against IL-2 (Denileukin diftitox)
mTOR inhibitors
- Everolimus
- Temsirolimus
hedgehog inhibitors
- Sonidegib
- Vismodegib
CDK inhibitor (Palbociclib
Ribociclib)

Monoclonal antibodies for tumors

Tumor
("-t(u[m])-")

Human ("-tumu-")	Adecatumumab^§ Ascrinvacumab^§ Cixutumumab^§ Conatumumab^§ Daratumumab Drozitumab^§ Duligotumab^§ Dusigitumab^§ Enfortumab vedotin^§ Enoticumab^§ Figitumumab^§ Ganitumab^† Glembatumumab vedotin^§ Intetumumab^§ Ipilimumab Iratumumab^§ Icrucumab^§ Lexatumumab^§ Lucatumumab^§ Mapatumumab^§ Narnatumab^§ Necitumumab Nesvacumab^§ Ofatumumab Olaratumab^† Panitumumab Patritumab^§ Pritumumab^§ Radretumab^§ Ramucirumab Rilotumumab^† Robatumumab^§ Seribantumab^§ Tarextumab^§ Teprotumumab^§ Tovetumab^§ Vantictumab^§ Vesencumab^§ Votumumab^§ Zalutumumab^† "-melu-" (melanoma) Flanvotumab^§
Mouse ("-tumo-")	Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab Detumomab Ibritumomab tiuxetan Minretumomab Mitumomab Moxetumomab pasudotox Naptumomab estafenatox Nofetumomab merpentan Pemtumomab^† Pintumomab Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Tenatumomab Tositumomab 3F8 "-govo-" (ovarian tumor) Abagovomab Igovomab Oregovomab "-pro-" (prostate tumor) Capromab pendetide "-colo-" (colonic tumor) Edrecolomab Nacolomab tafenatox
Chimeric ("-tuxi-")	Amatuximab^§ Bavituximab^§ Brentuximab vedotin Cetuximab Derlotuximab biotin^§ Dinutuximab Ensituximab^§ Futuximab^§ Girentuximab^† Indatuximab ravtansine^§ Isatuximab^† Margetuximab^† Rituximab^# Siltuximab Ublituximab^§ "-mexi-" (melanoma): Ecromeximab^§
Humanized ("-tuzu-")	Abituzumab^§ Alemtuzumab Bevacizumab Bivatuzumab mertansine^§ Brontictuzumab^§ Cantuzumab mertansine^§ Cantuzumab ravtansine^§ Citatuzumab bogatox^§ Clivatuzumab tetraxetan Dacetuzumab^§ Demcizumab^§ Dalotuzumab^§ Denintuzumab mafodotin^§ Elotuzumab Emactuzumab^§ Emibetuzumab^§ Enoblituzumab^§ Etaracizumab^§ Farletuzumab^§ Ficlatuzumab^§ Gemtuzumab ozogamicin^‡ Imgatuzumab^§ Inotuzumab ozogamicin^† Labetuzumab^§ Lifastuzumab vedotin^§ Lintuzumab^§ Lorvotuzumab mertansine^§ Lumretuzumab^§ Matuzumab^§ Milatuzumab^§ Nimotuzumab^† Obinutuzumab Ocaratuzumab^§ Otlertuzumab^§ Onartuzumab^§ Oportuzumab monatox^§ Parsatuzumab^§ Pertuzumab Pinatuzumab vedotin^§ Polatuzumab vedotin^§ Sibrotuzumab^§ Simtuzumab^§ Tacatuzumab tetraxetan^§ Tigatuzumab^§ Trastuzumab Tucotuzumab celmoleukin^§ Vandortuzumab vedotin^§ Vanucizumab^§ Veltuzumab^§ Vorsetuzumab mafodotin^§ "-gozu-" (ovarian tumor) Sofituzumab vedotin^§
Rat/mouse hybrid ("-tumaxo-")	Catumaxomab Ertumaxomab^§
Chimeric + humanized ("-tuxizu-")	Depatuxizumab mafodotin^§ Ontuxizumab^§
Veterinary ("-tuvet-")	Blontuvetmab^§ Tamtuvetmab^§

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

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