Tumor-targeted superagonistic cd28 antigen binding molecules

An antigen-binding molecule, hyper-agonistic technology, used in anti-tumor drugs, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, etc.

Pending Publication Date: 2021-08-20
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the intrinsic tendency of bispecific scFvs to form multimeric constructs, reported bispecific scFvs possess "hyperagonistic" activity despite the use of conventional CD28 agonistic binders 9.3

Method used

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  • Tumor-targeted superagonistic cd28 antigen binding molecules
  • Tumor-targeted superagonistic cd28 antigen binding molecules
  • Tumor-targeted superagonistic cd28 antigen binding molecules

Examples

Experimental program
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example

[0436] The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above.

[0437] recombinant DNA technology

[0438] DNA was manipulated using standard methods, as described in Sambrook et al., Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. Molecular biology reagents were used according to the manufacturer's instructions. General information on the nucleotide sequences of human immunoglobulin light and heavy chains is given in the following reference: Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication No 91- 3242.

[0439] DNA sequencing

[0440] DNA sequence was determined by double-strand sequencing.

[0441] gene synthesis

[0442] If desired, the desired gene segments were generated by PCR using appropriate templates, or synthesize...

example 1

[0457] Generation and production of bispecific or trispecific antibodies targeting CD28 and fibroblast activation protein (FAP) or carcinoembryonic antigen (CEA)

[0458] 1.1 Cloning of bispecific or trispecific antibodies targeting CD28 and fibroblast activation protein (FAP) or carcinoembryonic antigen (CEA)

[0459] Antigen cloning :

[0460] A DNA fragment encoding the extracellular domain of human CD28 (Uniprot: P10747) (amino acids 1 to 134 of the mature protein) was inserted in-frame into two columns upstream of the fragment encoding the human IgG1 Fc fragment (which serves as a lysis and purification tag). in different mammalian hosts. One expression vector contains "hole" mutations in the Fc region and the other contains "knob" mutations with a C-terminal avi tag (GLNDIFEAQKIEWHE, SEQ ID NO: 162), which can be performed when co-expressed with Bir A biotin ligase Specific biotinylation reaction. Additionally, both Fc fragments contain the PG-LALA mutation. Both v...

example 2

[0502] Binding and Kinetic Analysis of Bispecific Antibodies Targeting CD28 and Fibroblast Activation Protein (FAP) or Carcinoembryonic Antigen (CEA) Bispecific or Trispecific Antibodies

[0503] 2.1 Binding of bispecific antibodies targeting CD28 and fibroblast activation protein (FAP) to cells expressing FAP and CD28

[0504] 3T3-huFAP cells (clone 19) expressing human fibroblast activation protein (huFAP) were used to test the binding of the bispecific FAP-CD28 molecule. This cell line was generated by transfecting the mouse embryonic fibroblast NIH / 3T3 cell line (ATCC CRL-1658) with the expression vector pETR4921 under 1.5 μg / mL puromycin selection to express huFAP. Binding to human CD28 was tested with CHO cells expressing human CD28 (parental cell line CHO-k1 ATCC #CCL-61, modified to stably overexpress human CD28).

[0505] To assess binding, cells were harvested, counted, checked for viability, and resuspended in FACS buffer (eBioscience, cat. no. 00-4222-26) at 2.5E5...

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Abstract

The present invention relates to tumor targeted superagonistic antigen binding molecules capable of multivalent binding to CD28, methods for their production, pharmaceutical compositions containing these antibodies, and methods of using the same.

Description

technical field [0001] The present invention relates to tumor-targeting hyperagonist CD28 antigen-binding molecules, methods for their production, pharmaceutical compositions containing these molecules, and their use as immunomodulators in cancer therapy. Background technique [0002] Cancer immunotherapy is emerging as an increasingly effective treatment option that can produce dramatic and durable responses in cancer types such as melanoma, non-small cell lung cancer, and renal cell carcinoma. This is largely driven by the success of several immune checkpoint blockade drugs, including anti-PD-1 (eg, Keytruda, Merck; Opdivo, BMS), anti-CTLA-4 (eg, Yervoy, BMS), and anti-PD - L1 (eg, Tecentriq, Roche). These drugs are likely to serve as the standard of care for many cancer types, or as the basis for combination therapies, however, only a small proportion of patients (<25%) benefit from such therapies. Furthermore, various cancers (prostate, colorectal, pancreatic, sarco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30C07K16/40A61P35/00
CPCC07K16/2818C07K16/3007C07K16/40C07K2317/31C07K2317/35C07K2317/52C07K2317/70C07K2317/71C07K2317/73C07K2317/75A61P35/00A61K38/00A61K2039/505C07K2317/55C07K2317/565
Inventor S·加塞G·乔治斯T·霍弗C·克莱因J·T·托姆P·尤马纳
Owner F HOFFMANN LA ROCHE & CO AG
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