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| Primary information |
|---|
| ID | 15531 |
| Therapeutic ID | Th1606 |
| Protein Name | Lanadelumab |
| Sequence | >Th1606_Lanadelumab
EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYIMMWVRQAPGKGLEWVSGIYSSGGITVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAYRRIGVPRRDEFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
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| Molecular Weight | 146000 |
| Chemical Formula | C6468H10016N1728O2012S47 |
| Isoelectric Point | 6.1-8.5 |
| Hydrophobicity | NA |
| Melting point | 80-90 ºC (based on IgG properties) |
| Half-life | Lanadelumab has a prolonged half-life which is typical of a human monoclonal antibody and it ranged from 13.8 to 15 days.[A38677] |
| Description | Lanadelumab, also known as DX-2930, is a human IgG1 monoclonal antibody designed for subcutaneous self-injection.[L4538] It is a fully human immunoglobulin, k-light-chain made in recombinant Chinese Hamster Ovary cells.[L4537] The FDA and EU granted the designation of priority review, breakthrough therapy and orphan drug for rare diseases based on the results of the reported clinical trials.[A38676] Lanadelumab was developed by Shire and FDA approved on August 28, 2018.[L4537] |
| Indication/Disease | Lanadelumab is indicated for the prophylaxis treatment to prevent attacks in patients 12 years and older with hereditary angioedema.[L4537] The hereditary angioedema (HEA) is an autosomal dominant disorder resulted from the presence of C1 deficiency. Some reports have indicated a high prevalence of cases that result from spontaneous mutations which can be inherited. This condition is manifested by attacks of subcutaneous or submucosal edema in the face, larynx, GI tract, limbs or genitalia. From all the types of attacks, the most serious is the laryngeal as it can compromise the airway. The rest of the attacks are accompanied by pain and considerable dysfunction.[A38679] |
| Pharmacodynamics | In phase 1 studies, the level of kininogen, the substrate of kallikrein, was studied as a marker of kallikrein activity. In patients with C1 deficiency, the level of cleaved kininogen is 4-fold higher when compared with C1-normal individuals. When lanadelumab was administered, the levels of cleaved kininogen were significantly reduced with a dose of 300 and 400 mg of lanadelumab with a maximum reduction at day 22 corresponding with time for maximum concentration. This maximum reduction corresponded with the normal levels of cleaved kininogen. Similarly, the decreases of cleaved kininogen corresponded as well with reductions in the levels of the activated factor XII.[A38677] Clinically, the attacks of angioedema completely vanished in the patients receiving a dose of 300 mg of lanadelumab. In other doses such as 400 mg and combo 300/400 mg the attack reduction reached 90%.[A38677] In phase 3 clinical trials (HELP study, lanadelumab showed an attack rate reduction of over 70% for all three different dose regimes.[A38676] |
| Mechanism of Action | Lanadelumab is a plasma kallikrein inhibitor. This enzyme works by cleaving high molecular weight kininogen to generate the pro-inflammatory peptide bradykinin which is a potent vasodilator. The activity of plasma kallikrein is regulated by the activity of C1-inhibitor and thus, the patients that are deficient in C1 are known to be correlated to excessive production of bradykinin which will further lead to fatal angioedema.[A19127] Hence, lanadelumab occludes the proteolytic active site of plasma kallikrein, preventing the cleavage of kininogen to bradykinin. It is a selective inhibitor as it has been reported that lanadelumab does not bind to prekallikrein or to inhibit any other serine proteases.[A38679] The activity of lanadelumab works as an additional checkpoint for the patients suffering from C1 deficiency. |
| Toxicity | In clinical trials, the apparition of antidrug antibodies was nos significant and from those who expressed it, none were neutralizing.[A38677] No significant toxicities related to the administration of lanadelumab have been reported.[A38679] Studies regarding the carcinogenic potential or overdosage effect have not been performed. Fertility studies show no effect on reproductive organs.[FDA label] |
| Metabolism | Because lanadelumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes. |
| Absorption | The drug levels of lanadelumab are dose-dependent and thus, the maximum plasma concentration increased correspondingly with an increased dosage. The Cmax and AUC ranged from 3800 to 45000 ng/ml and from 64000 to 762000 ng.day/ml respectively for concentrations from 30 to 400 mg. As well, sustained quantifiable drug concentration was observed through day 120.[A38677] The bioavailability of lanadelumab is of approximately 66% with a time to reach peak drug concentration of approximately 7 days.[A38679] |
| The reported volume of distribution of lanadelumab is in the range of 12 to 16 L which variates according to the dose administered.[A38679] |
| Clearance | The apparent total plasma clearance after extravascular administration ranges between 18 and 25 ml/h.[A38677] |
| Categories | Antibodies |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Plasma kallikrein |
| Brand Name | Takhzyro |
| Company | Takeda |
| Brand Description | Takeda |
| Prescribed For | Subcutaneous |
| Chemical Name | 300 mg / 2 mL |
| Formulation | None. |
| Physical Appearance | injection site reactions: pain, redness, bruising, bleeding, itching, a hard lump, numbness and tingling, warmth, swelling, and rash) upper respiratory infections, headache, rash, muscle pain, dizziness, and diarrhea |
| Route of Administration | Takhzyro is a monoclonal antibody that works by reducing the activity of an enzyme that is uncontrolled in people with hereditary angioedema (a rare genetic immune system disorder). Takhzyro is used to prevent attacks of hereditary angioedema (HAE) in people who are at least 12 years old. Warnings Follow... |
| Recommended Dosage | Takhzyro is a prescription medicine used to treat the symptoms of Hereditary Angioedema. Takhzyro may be used alone or with other medications. |
| Contraindication | NA |
| Side Effects | Lanadelumab-flyo is non-plasma derived, recombinant, fully human, monoclonal antibody (IgG1/κ-light chain) produced in Chinese Hamster Ovary (CHO) cells. Based on the amino acid sequence, the molecular weight of the non-glycosylated lanadelumab-flyo is 146 kDa. The calculated molecular mass of the fully reduced light chain is 23 kDa. The calculated molecular mass of the fully reduced and non-glycosylated heavy chain is 49 kDa. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |