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Combination of c-met inhibitor with antibody molecule to pd-1 and uses thereof

A technology of PD-1 and antibody molecules, applied in the direction of antibody medical components, antibodies, drug combinations, etc., can solve the lack of MYPPY motifs and other problems

Inactive Publication Date: 2018-10-23
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif (SEQ ID NO:236) important for B7-1 and B7-2 binding

Method used

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  • Combination of c-met inhibitor with antibody molecule to pd-1 and uses thereof
  • Combination of c-met inhibitor with antibody molecule to pd-1 and uses thereof
  • Combination of c-met inhibitor with antibody molecule to pd-1 and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0761] Embodiment 1: the pharmacokinetic analysis of flat dosing regimen

[0762] Based on pharmacokinetic (PK) modeling, flat doses are expected to provide exposure to patients at appropriate Cmin concentrations. More than 99.5% of patients will be above EC50 and more than 93% of patients will be above EC90. Steady-state mean Cmin predicted for the exemplary anti-PD-1 antibody molecule using 300 mg every three weeks (Q3W) or 400 mg every four weeks (Q4W) is expected to average above 20 ug / mL (maximum body weight, 150 kg).

[0763] Table 5 Exemplary PK Parameters Based on Flat Dosing Regimen

[0764]

[0765] The expected mean steady-state Cmin concentration of the exemplary anti-PD-1 antibody molecule observed with either dose / regimen (300mg q3w or 400mg q4w) would be about 77-fold higher than the EC50 (0.42ug / mL) and about 77 times higher than the EC90 8.6 times higher. Ex vivo efficacy is based on IL-2 changes in the SEB ex vivo assay.

[0766] For 300mg Q3W or 400mg...

Embodiment 2

[0769] Example 2: Phase Ib / II open-label, multi-center study of Capmatinib combined with anti-PD-1 antibody molecule ("Antibody A", detailed below) or antibody A single drug in the treatment of advanced hepatocellular carcinoma

[0770] antibody molecule A

[0771] Antibody molecule A is a high affinity fully humanized anti-human PD-1 monoclonal antibody belonging to the IgG4 / κ isotype subclass. It is expressed in a Chinese hamster ovary cell line (CHO-C8TD) and consists of two heavy chains and two light chains. Both heavy chains of antibody molecule A contain oligosaccharide chains attached to the protein backbone at Asn294.

[0772] The amino acid sequences of the light chain (220 amino acids) and heavy chain (443 amino acids) deduced from the DNA sequences are shown in Figure 15 and Figure 16 .

[0773] Table 6 lists the expected disulfide bonds derived from the primary sequence.

[0774] Table 6 Expected disulfide bonds

[0775]

[0776] Based on the amino acid comp...

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Abstract

The present invention relates to a pharmaceutical combination which comprises (a) at least one antibody molecule (e.g., humanized antibody molecules) that bind to Programmed Death 1 (PD-1), and (b) atleast one c-Met receptor tyrosine kinase inhibitor or pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential administration for the treatment of a proliferative disease, particularly a c-Met dependent proliferative disease; a pharmaceutical composition comprising such combination; a method of treating a subject having a proliferative disease comprising administration of said combination to a subject in need thereof; use of such combination for the treatment of proliferative disease; and a commercial package comprising such combination.

Description

technical field [0001] The present invention relates to a pharmaceutical combination comprising (a) at least one antibody molecule (e.g., a humanized antibody molecule) that binds programmed death molecule 1 (PD-1), and (b) at least one c-Met receptor A body tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential administration for the treatment of proliferative diseases, particularly c-Met-dependent proliferative diseases; a medicament comprising said combination Compositions; methods of treating a subject with a proliferative disease comprising administering the combination to a subject in need thereof; use of the combination to treat a proliferative disease; and a commercial package comprising the combination. Background technique [0002] The ability of T cells to mediate an immune response against an antigen requires two distinct signaling interactions (Viglietta, V et al. (2007) Neurotherapeutics 4: 666-675; Kor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/28A61K39/00
CPCA61K39/39558C07K16/2818A61K31/4725A61K2039/545C07K2317/21C07K2317/92A61P35/00A61P35/02A61P35/04A61K2300/00A61K9/0019A61K9/0053A61K31/53A61K39/3955
Inventor S·比利克D·R·小霍华德J·S·卡梅伦
Owner NOVARTIS AG
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