As a leading service provider focused on drug development, BOC Sciences has been supporting customers at the forefront of drug conjugates. Immunotoxins, an antibody-toxin molecules, have been developed as potent anti-cancer therapeutics. We provide antibody-exotoxin conjugation services by chemical or biological methods to meet project needs of our customers. Our comprehensive drug conjugation platform will provide quality services to assist our clients in drug development.
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Antibody-exotoxin conjugates (AExCs), also known as the immunotoxins, are protein-based therapeutics comprising at least two functional domains, one allowing them to bind specific target cells, and one that kills the cells following internalization. AExC consists of a toxin from bacteria or plants and a targeting module.
|Source||Mechanism of action|
|Pseudomonas exotoxin||Pseudomonas aeruginosa||inhibits protein synthesis|
|Diphtheria toxin||Corynebacterium diphtheriae||inhibits protein synthesis|
|Ricin||castor oil plant||depurinates a critical adenine in 28S rRNA|
Table 1 three toxins: PE, DT, ricin
Fig. 1 Conjugation of trastuzumab and PE24-AzF (Lee, 2019)
AExCs contained an antibody and a protein toxin chemically conjugated together to target antigen-bearing cells for catalytic destruction. For example, PE-based AExCs target to a cell-surface receptor (CD91) and translocates into the cytoplasm via endocytosis. PE ADP-ribosylate elongation factor 2 halts protein synthesis at the elongation step, which results in finally cellular death.
AExCs can be also produced by recombinant protein engineering. One of the intensively studied AExCs is a fusion protein consisting of an antibody fragment and PE. Given the complexity of recombinant protein fusions, AExC can be prepared by non-specific chemical cross-linking between antibody and exotoxin. As an alternative, the introduction of a bio-orthogonally reactive unnatural amino acid into protein is effective conjugation method.
AEXCs can be constructed by linking toxins to targeting molecules through chemical or biological strategies. Early AEXCs were constructed by using chemical crosslinking agents to attach intact toxins to intact antibodies. There were also AEXCs that use modified toxins lacking receptor-binding domains. Early AEXCs had non-specific toxicity due to retention of the binding domain of the toxin, until the toxin binding domains were deleted. Due to the development of molecular cloning techniques that produce gene fusions and prokaryotic expression systems, antibody-toxin molecules can be fused together. It is no longer necessary to purify large amounts of antibodies and toxins and then combine the two with chemical cross linkers. The first recombinant antibody-toxin fusion protein came with the expression of scFv fragments in E. coli that retained antigen binding.
We provide various conjugation methods to produce AExC, these protein-protein cross-linking approaches include but not limited to:
The representative AExC is moxetumomab pasudotox, a conjugate that combines an anti-CD22 monoclonal antibody and the PE38 (a 38 kDa truncated form of PE), which has been approved by the FDA for the treatment of hairy cell leukemia (HCL). Another approved AExC is loncastuximab tesirine, consisting of a humanized anti-CD19 antibody and pyrrolobenzodiazepine dimeric toxin SG3199, which was approved by the FDA in 2021 for the treatment of diffuse large B-cell lymphoma (DLBCL).