Murine mAbs

Murine mAbs are antibodies of murine origin. The first murine mAb to be approved for clinical use was muromonab-CD3 (Orthoclone OKT3 ), an mAb with CD3 on Tcells as the molecular target, and used in organ transplantation. 

The therapeutic application of antibodies of non-human origin may cause problems because murine mAbs are recognized by the human immune system as extrinsic substances. In general, the first administration of 100% murine mAbs is well tolerated. However, it can induce the production of specific anti-antibodies by the human body, the so-called human anti-murine antibodies (HAMAs), against the murine mAbs. Repeated administration of 100% murine mAbs may cause an immune response with influenza-like symptoms and even severe states of shock. 

New technology developed during the 1980s allowed the development of the following antibody species. 

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CEA-Scan (Arcitumomab, murine Mab fragment (Fab), directed against human CEA)... 

MyoScint (Imiciromab-Pentetate, murine Mab fragment directed against human cardiac myosin)... 

OncoScint CR/OV (Satumomab Pendetide, murine Mab directed against TAG-72, a high molecular weight tumour associated glycoprotein)... 

Orthoclone OKT3 (Muromomab CD3, murine Mab directed against the T-lymphocyte surface antigen CD3)... 

Tecnemab KI (murine Mab fragments (Fab/ Sorin Fab2 mix) directed against HMW-MAA, i.e. high molecular weight melanoma-associated antigen)... 

As discussed previously, murine antibodies have limitations. The next phase of development is to make these murine MAbs more like human antibodies, by using genetic engineering techniques. A recent approach is to humanize the antibodies to reduce HAMA and improve the avidity of the MAbs (avidity... 

In mice with human breast carcinoma xenografts, a humanized IgG anti-HER-2 MAb eradicated well-established tumours [58]. In addition, a humanized version of an IgG anti-CD33 MAb (HuM 195) mediated ADCC in vitro [59] and had an 8.6-fold higher avidity than the parent murine Mab. Recombinant antibody fragments may have valnable properties as discnssed above, bnt their biophysical behavionr, prodnction yield and low thermostability leaves mnch to be desired and thereby limits their nsefnlness for in-vivo applications so far [60]. One possibility to improve these characteristics of scFv fragments with snboptimal stability and/or folding yield, is the grafting of their CDRs onto the framework of a different, more stable scFv [61,62]. 

Indimacis 125 (Igovomab, murine Mab fragment (Fab2) directed against the tumour-associated antigen CA 125)... 

ProstaScint (Capromab Pentetate, C5dogen murine Mab directed against the tumour surface antigen PSMA)... 

Whether humanization satisfactorily reduces the immunogenicity of a murine Mab ultimately requires a direct comparison of the humanized and mouse anti-... 

Sodium sulfate precipitation is not usually recommended for most murine MAbs because mouse/rat IgG can be degraded by the relatively high temperature (25°C) used during this procedure. If lipid contamination of ascitic fluids is a particular problem, add silicone dioxide powder (15 mg/mL), and centrifuge for 20 min at 2000g. Use the method described in Chapter 10, Section 3.2.1. 

Fractionation using diethylaminoethyl (DEAE) (or several other anion exchangers) does not work well for murine MAbs, because each MAb has a different isoelectric point that often overlaps with many other proteins present in the MAb-containmg preparation, except of course for those MAbs that happen to have a suitable charge. However, conditions can be tailored if necessary. Strong anion exchangers may be used as a generic method for any MAb. Two methods are described in Chapter 10, Section 3.3.2. 

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