Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates

Aβ is the toxic amyloid polypeptide responsible for Alzheimer’s disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-Aβ recognition complexes to get insights into their structural and dynamic properties and gammabody-Aβ recognitions. Among many heterogeneous binding modes, we focused on two gammabody-Aβ recognition scenarios: recognition through Aβ β-sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted Aβ sequence to interact with the Aβ fibril, while CDR1/CDR2 loops have very little contact. The gammabody-Aβ complexes with backbone binding mode are more stable, explaining the gammabody’s specificity towards the C-terminal Aβ sequence.

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Faculty Opinions recommendation of Crystal structure of a shark single-domain antibody V region in complex with lysozyme.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1024018.285841 ◽

2005 ◽

Author(s):

Christopher Garcia

Keyword(s):

Crystal Structure ◽

Single Domain ◽

Single Domain Antibody ◽

Domain Antibody ◽

V Region

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CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch

Leukemia ◽

10.1038/s41375-021-01208-2 ◽

2021 ◽

Author(s):

Xin He ◽

Zijie Feng ◽

Jian Ma ◽

Xuyao Zhang ◽

Sunbin Ling ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Domain ◽

Single Domain Antibody ◽

Car T Cells ◽

Domain Antibody ◽

Car T ◽

Acute Myeloid

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Production, characterization and in-vitro applications of single-domain antibody against thyroglobulin selected from novel T7 phage display library

Journal of Immunological Methods ◽

10.1016/j.jim.2021.112990 ◽

2021 ◽

Vol 492 ◽

pp. 112990

Author(s):

Jothivel Kumarasamy ◽

Samar Kumar Ghorui ◽

Chandrakala Gholve ◽

Bharti Jain ◽

Yogesh Dhekale ◽

...

Keyword(s):

Phage Display ◽

Phage Display Library ◽

Single Domain ◽

Single Domain Antibody ◽

Domain Antibody ◽

T7 Phage Display ◽

T7 Phage

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A Single-Domain Antibody-Based Anti-PSMA Recombinant Immunotoxin Exhibits Specificity and Efficacy for Prostate Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22115501 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5501

Author(s):

Yutong Xing ◽

Keyuan Xu ◽

Shixiong Li ◽

Li Cao ◽

Yue Nan ◽

...

Keyword(s):

Prostate Cancer ◽

Animal Studies ◽

Single Domain ◽

Soluble Form ◽

Therapeutic Window ◽

Single Domain Antibody ◽

Pseudomonas Exotoxin A ◽

Simple Strategy ◽

Domain Antibody ◽

Recombinant Immunotoxin

Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.

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