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Literature Analysis (IF 45.8) | Relationship Between CAR-T Therapy and Bispecific Antibodies
2025-12-31
CAR-T TherapyNEWS
The paper "Design of high-specificity binders for peptide–MHC-I complexes," published in Science, was conducted by Nobel laureate David Baker's team. This research successfully employed deep learning tools to de novo design small proteins that bind with high specificity to peptide-MHC class I complexes (pMHCs), opening a new pathway for precise immunotherapy of cancer and viral diseases.
MHC class I complexes are a type of T-cell surface receptor (TCR) that can effectively activate T cells, prompting them to secrete perforin or granzymes for cell killing. Similarly, CAR-T therapy leverages the cytotoxic function of T cells to achieve targeted elimination of cancer cells. Specifically, this involves collecting a patient's peripheral blood T lymphocytes, genetically engineering them to express a chimeric antigen receptor (CAR) on their surface, and then reinfusing the modified T cells back into the patient. As the CAR can specifically recognize antigens on the surface of cancer cells, it directs the engineered T cells to perform targeted killing of the cancer cells.
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Peptide ScreeningNEWS
Conventional CAR sequences can be obtained by immunizing animals with specific antigens found on the surface of cancer cells, followed by antibody library construction and screening. However, this process is time-consuming.
Peptide screening offers an alternative by bypassing animal immunization. This approach involves directly screening random peptide libraries to identify peptide sequences with good affinity. These identified peptide sequences can then serve as the CAR domain for engineering T cells, generating a broader pool of candidate therapeutic T cells. We provide a variety of ready-to-use peptide library kits (e.g., random 7-mer, 12-mer, cyclic 7-mer libraries) and custom M13/T7 phage display library kits to assist clients in rapidly discovering protein ligands, enzyme substrates, and highly specific antibodies, providing a solid foundation for your innovative R&D.
Peptide Library Screening ProcessNEWS
Random Peptide Library Construction
Based on phage display technology, DNA fragments encoding random peptide sequences are cloned into a specific coat protein gene of a phage genome. For example, for M13 phage libraries, the peptides are typically fused to the pIII or pVIII coat protein gene. This results in each phage particle displaying a unique random peptide on its surface, while the genetic information encoding that peptide is contained within the phage particle, establishing a phenotype-genotype linkage.
Affinity Screening (Biopanning)
This process selects phage particles that bind to a target molecule from a vast library. The specific steps are as follows:
Binding/Adsorption
The target molecule is immobilized on a solid support (e.g., ELISA plate, magnetic beads). The phage-displayed peptide library is then added and allowed to incubate.
Washing
Non-specific or weakly bound phages are removed through a series of washes.
Elution
Specifically bound phages are eluted from the target using an appropriate elution buffer (e.g., low-pH glycine-HCl solution).
Amplification
The eluted phages are used to infect E. coli host cells (e.g., strain TG1) for amplification and subsequent harvest. The titer of both the eluted and amplified phage populations is typically measured.
Iterative Rounds of Screening
Usually, 3 to 5 rounds of this "binding-washing-elution-amplification" cycle are performed to progressively enrich for phage clones with increasingly higher affinity and specificity for the target.
Identification and Analysis
After the final screening round, individual clones from the eluted phage pool are characterized.
Binding Validation
Single colonies are picked from a bacterial plate, the corresponding phage is amplified and purified, and binding to the target is confirmed using methods like phage ELISA.
DNA Sequencing
Clones showing positive binding are subjected to Sanger sequencing. The obtained DNA sequences are analyzed to determine the amino acid sequence of the displayed peptide.
Affinity Analysis
For further characterization, positive peptide sequences may be chemically synthesized. Depending on the target type and sample quality, various methods (e.g., Surface Plasmon Resonance/SPR, ELISA) can then be used to determine binding affinity.
Alpha Lifetech has extensive expertise in peptide library construction and screening services. In addition to our existing peptide libraries (such as random 7-mer, 12-mer, cyclic 7-mer, and M13/T7 phage libraries), we offer customized peptide library design and screening services tailored to specific experimental needs. We are also continuously exploring downstream applications for identified peptides to create more possibilities for our clients.
FAQsNEWS
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1. What are the types of peptide libraries?
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2. When constructing a randomized library, how is the random region designed?
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3. How is the quality of a peptide library assessed?
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4. How can non-specific binding (false positives) be reduced during the screening process?
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5. Why are high-affinity peptides sometimes not isolated during screening?
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6. What screening strategies can be used for difficult targets (e.g., GPCRs, ion channels)?
Use of Native Fragment Libraries:
Construct libraries derived from natural protein sequences, which may be more likely to contain peptides that interact with complex membrane proteins.
Whole-Cell Screening:
Instead of purifying the target protein, perform screening directly on the surface of live cells expressing the target. This ensures the target is in its native conformation and membrane environment.
Competitive Screening:
Include known ligands or antibodies during the screening process to competitively select for peptides binding to novel epitopes.
ReferenceNEWS
[1] Chen R, Chen L, Wang C, Zhu H, Gu L, Li Y, Xiong X, Chen G, Jian Z. CAR-T treatment for cancer: prospects and challenges. Front Oncol. 2023 Dec 5;13:1288383.
[2] Sawada T, Oyama R, Tanaka M, Serizawa T. Discovery of Surfactant-Like Peptides from a Phage-Displayed Peptide Library. Viruses. 2020 Dec 15;12(12):1442.
[3] Ryvkin A, Ashkenazy H, Weiss-Ottolenghi Y, Piller C, Pupko T, Gershoni JM. Phage display peptide libraries: deviations from randomness and correctives. Nucleic Acids Res. 2018 May 18;46(9):e52.