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Table 2 Overview on the nanobody-based applications, their advantages and drawbacks, as well as solutions at present

From: Nanobody: a promising toolkit for molecular imaging and disease therapy

Function and target Combined with Advantages Disadvantages Solution References
Antagonist:
EGFR,
CXCR4,
P2X7,
HGF
 - (i) Small size
(ii) High solubility and stability
(iii) Excellent tissue penetration
(iv) Recognizing new targets
(v) Using together with mAbs
(i) Fast blood clearance
(ii) High renal uptake
(iii) Lack of Fc
(iv) Immunogenicity
(i) Constructing multivalent nanobody
(ii) Co-injecting with cationic amino acids
(iii) Conjugating with an anti-albumin unit
(iv) Linking with effector domains
[35, 41]
Nanobody-based radionuclide:
HER2
225Ac,131I, 177Lu (i) Fast blood clearance
(ii) Suited for conjugation
(i) High renal uptake
(ii) Radiation toxicity to healthy cells
(i) Constructing multivalent nanobody, co-injecting with cationic amino acids, conjugating with an anti-albumin unit
(ii) Linking with residualizing prosthetic group such as SGMIB
(iii) Selecting high-affinity and high-internalization nanobody
[82, 83]
Nanobody-mediated drug delivery system:  EGFR, HER2 (i) Pharmeceutic carriers
(ii) Chemotherapeutic drugs
(i) Can act as antagonist itself
(ii) High specificity  (iii) Suited for conjugation
(i) Fast blood clearance
(ii) The drug can damage normal cells
(i) Encapsulation in carriers,
(ii) PEGylation
[86, 87]
Nanobody-based immunotoxin:
EGFR, CD7
(i) Plant toxins
(ii) Bacterial protein toxins such as PE and DT
(i) Lethal to cells in all phases
(ii) High efficacy
(i) Immunogenicity
(ii) Lysosome-sensitive sites in toxin part
(i) Linking nanobody with humanized nanobody scaffold
(ii) Deleting lysosome-sensitive sites
[98,99,100]
Nanobody-peptide fusions:
EGFR, DR, CEA
(i) The ligand of death receptor (TRAIL)
(ii) Fc domains
(iii) Cytokine
(i) Inducing ADCC and CDC
(ii) Specifically recruiting effector cells to lesions
Fast blood clearance (i) Constructing multivalent or nanobody,
(ii) Glycosylation modification
(iii) Crucial amino acid mutation in FR2
[17, 102,103,104]