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Co-formulations of Anti-lag3 antibodies and Anti-pd-1 antibodies

A PD-1, preparation technology, applied in the field of therapeutic antibody preparation, can solve problems such as impaired immune response, weakened T cell activation and immune surveillance evasion

Pending Publication Date: 2021-08-27
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells to attenuate T-cell activation and evasion of immune surveillance, thereby resulting in impaired immune responses against tumors

Method used

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  • Co-formulations of Anti-lag3 antibodies and Anti-pd-1 antibodies
  • Co-formulations of Anti-lag3 antibodies and Anti-pd-1 antibodies
  • Co-formulations of Anti-lag3 antibodies and Anti-pd-1 antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0341] Example 1: Study of Conditions to Reduce Self-Association of Anti-LAG3 Antibody Ab6

[0342] Diffusion interaction parameter (k D )Measurement

[0343] B found in 10 mM histidine pH 5.6 22 is negative, which indicates the intrinsic property of molecular self-association. It was found that the presence of 50 mM sodium chloride in 10 mM histidine pH 5.6 increased the diffusion interaction parameter (KD) of anti-LAG3 antibody Ab6 (SEQ ID NO: 35 and 57, light chain and heavy chain) or decreased its self-interaction, Improved its relative solubility and reduced turbidity (OD350), such as Figure 12 shown. In the presence of 40 mM L-arginine hydrochloride, the anti-LAG3 antibody was studied at 10 mM histidine pH using diffusion interaction parameters (KD), turbidity (OD350) and relative solubility (% PEG midpoint) assays. Stability in 5.6. Such as Figure 13 As shown, the self-interaction and turbidity were found to be drastically reduced, while the relative solubi...

Embodiment 2

[0367] Example 2: Preformulation Screening with Charged Species (Salts and Amino Acids) of Anti-LAG3 Antibody Ab6 Formulations

[0368] To evaluate the stability of anti-LAG3 antibodies in the presence of charged species (salts and amino acids), ten formulations listed in Table 5 were prepared and screened for the physicochemical properties of anti-LAG3 antibodies by high-throughput analysis The change. Formulations were properly sealed in 96-well plates and stressed in a dry heat oven at 50 °C for 10 days. Changes in the physicochemical properties of the anti-LAG3 antibodies were also evaluated for heat-stressed samples. A 20 mM concentration of L-aspartic acid or L-glutamic acid was chosen based on its solubility limit.

[0369]

[0370] Turbidity (OD 350 ) scheme

[0371] The turbidity (OD) of nine preparations was evaluated using an ultraviolet (UV) absorption spectrophotometer 350 ). UV absorbance of samples was measured at a wavelength of 350 nm in a 96-well...

Embodiment 3

[0383] Example 3: Screening of Stabilizers for Anti-LAG3 Antibody Ab6 Preparations

[0384] To evaluate the anti-LAG3 antibody Ab6 (25 mg / mL in 10 mM L-histidine, 70 mM L-arginine hydrochloride or in 70 mM sodium chloride) in the presence of different stabilizers such as sugars and polyols , pH 5.8), prepared eleven formulations as listed in Table 6.

[0385]

[0386] Ultra Performance Size Exclusion Chromatography (UP-SEC)

[0387] The purity of the samples was assessed by UP-SEC, in which the percentage of monomer was determined, as well as the percentage of high molecular weight species (HMW) and late eluting peaks (LMW species). UP-SEC was performed on a Waters Acquity UPLC system H class Bio by diluting the sample to 1.0 mg / mL in mobile phase (100 mM phosphate, 100 mM sodium chloride, pH 7.0). The column temperature was maintained at 25±3°C, and the flow rate was maintained at 0.5 mL / min, using isocratic elution. Diluted samples (5 μL) were injected into a UPLC eq...

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Abstract

The present invention provides co-formulations of anti-PD-1 antibodies and anti-LAG3 antibodies, and their use in treating various disorders.

Description

[0001] field of invention [0002] The present invention generally relates to formulations of therapeutic antibodies, and their use in the treatment of various disorders. [0003] Background of the invention [0004] Antibodies may differ slightly in the amino acid sequences of their constant domains or their framework sequences within their variable domains, but usually, their CDR sequences differ most significantly. Even antibodies that bind the same protein, the same polypeptide or even potentially the same epitope may contain entirely different CDR sequences. Therapeutic antibodies for use in humans can also be obtained from human germline antibody sequences or non-human (eg, rodent) germline antibody sequences, eg, in humanized antibodies, resulting in yet further diversity in the underlying sequence. These sequence differences could lead to potentially different stability in solution and different responsiveness to solution parameters. Furthermore, small changes in amin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61P35/00A61K39/00A61K39/44A61K9/19A61K47/26
CPCA61K39/00A61K47/26A61P35/00A61K45/06A61K9/19A61K9/0019A61K47/183A61K47/20A61K39/39591C07K16/2803C07K16/2818A61K47/22A61K47/12A61K9/08A61K2039/505A61K2300/00A61K47/10C07K2317/565C07K2317/92C07K2317/94
Inventor V·安托楚舒克P·G·德赛Y·克里希纳马查里S·S·桑加尼
Owner MERCK SHARP & DOHME BV
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