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Monoclonal Antibody Combinations that Present Synergistic Neutralizing Activity: A Platform for Next-Generation Anti-Toxin Drugs.

Diamant E, Torgeman A, Ozeri E, Zichel R - Toxins (Basel) (2015)

Bottom Line: Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations.Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation.The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, Israel Institute for Biological Research, Ness Ziona 7410001, Israel. erand@iibr.gov.il.

ABSTRACT
Monoclonal antibodies (MAbs) are among the fastest-growing therapeutics and are being developed for a broad range of indications, including the neutralization of toxins, bacteria and viruses. Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations. Moreover, the efficacy of an individual neutralizing MAb may significantly be hampered by the potential absence or modification of its target epitope in a mutant or subtype of the infectious agent. These limitations of individual neutralizing MAbs can be overcome by using oligoclonal combinations of several MAbs with different specificities to the target antigen. Studies conducted in our lab and by others show that such combined MAb preparation may present substantial synergy in its potency over the calculated additive potency of its individual MAb components. Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation. In this review, the synergistic neutralization properties of combined oligoclonal Ab preparations are described. The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed.

No MeSH data available.


Related in: MedlinePlus

Neutralizing activity of oligoclonal combinations [16]. Different BoNT doses were pre-incubated with combinations of equally diluted MAb ascites fluids (final dilution 1:200, equals ~25 µg/mL of IgG) and then injected into mice. The results indicate the maximal toxin dose that the mice could withstand. Anti-serotype B MAb results are zoomed separately. Anti-serotype A MAb panel: Seven [A-4, A-1, A-6, A-2, A-3, A-8, A-7], Four-EP [epitope recognition recognition-based MAbs A-4, A-1, A-3, and A-8], Four-Neut [neutralizing MAbs A-4, A-1, A-6, and A-2], Three [A-4, A-1, and A-8 or A-3]. Anti-serotype B MAb panel: Seven [B-4, B-2, B-1, B-3, B-6, B-5, and B-7], Two (B-1) [B-4 and B-1], and Two (B-5) [B-4 and B-5]. Anti-serotype E MAb panel: Eight [E-2, E-3, E-4, E-5, E-6, E-7, E-8, and E-1], Six-Neut [neutralizing MAbs E-2, E-3, E-4, E-5, E-7, and E-1], Four-EP [epitope recognition-based MAbs E-2, E-3, E-8, and E-1], and E-1.
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toxins-07-01854-f001: Neutralizing activity of oligoclonal combinations [16]. Different BoNT doses were pre-incubated with combinations of equally diluted MAb ascites fluids (final dilution 1:200, equals ~25 µg/mL of IgG) and then injected into mice. The results indicate the maximal toxin dose that the mice could withstand. Anti-serotype B MAb results are zoomed separately. Anti-serotype A MAb panel: Seven [A-4, A-1, A-6, A-2, A-3, A-8, A-7], Four-EP [epitope recognition recognition-based MAbs A-4, A-1, A-3, and A-8], Four-Neut [neutralizing MAbs A-4, A-1, A-6, and A-2], Three [A-4, A-1, and A-8 or A-3]. Anti-serotype B MAb panel: Seven [B-4, B-2, B-1, B-3, B-6, B-5, and B-7], Two (B-1) [B-4 and B-1], and Two (B-5) [B-4 and B-5]. Anti-serotype E MAb panel: Eight [E-2, E-3, E-4, E-5, E-6, E-7, E-8, and E-1], Six-Neut [neutralizing MAbs E-2, E-3, E-4, E-5, E-7, and E-1], Four-EP [epitope recognition-based MAbs E-2, E-3, E-8, and E-1], and E-1.

Mentions: Within each serotype-specific group, we produced neutralizing MAbs, the majority of which were protective against a toxin dose of 10 Mouse Lethal Dose 50% (MsLD50). Encouraged by these results, we sought to determine whether the MAb combinations in each serotype-specific group exhibited increased neutralizing activity. The best combination for anti-serotype E MAbs displayed a very high synergistic neutralizing activity of up to 400-fold over that of its components (Figure 1). The cocktail of anti-serotype A MAbs, which protected against 125,000 MsLD50 of toxin A, had a 154-fold improvement over the calculated additive effect of the mixture’s components.


Monoclonal Antibody Combinations that Present Synergistic Neutralizing Activity: A Platform for Next-Generation Anti-Toxin Drugs.

Diamant E, Torgeman A, Ozeri E, Zichel R - Toxins (Basel) (2015)

Neutralizing activity of oligoclonal combinations [16]. Different BoNT doses were pre-incubated with combinations of equally diluted MAb ascites fluids (final dilution 1:200, equals ~25 µg/mL of IgG) and then injected into mice. The results indicate the maximal toxin dose that the mice could withstand. Anti-serotype B MAb results are zoomed separately. Anti-serotype A MAb panel: Seven [A-4, A-1, A-6, A-2, A-3, A-8, A-7], Four-EP [epitope recognition recognition-based MAbs A-4, A-1, A-3, and A-8], Four-Neut [neutralizing MAbs A-4, A-1, A-6, and A-2], Three [A-4, A-1, and A-8 or A-3]. Anti-serotype B MAb panel: Seven [B-4, B-2, B-1, B-3, B-6, B-5, and B-7], Two (B-1) [B-4 and B-1], and Two (B-5) [B-4 and B-5]. Anti-serotype E MAb panel: Eight [E-2, E-3, E-4, E-5, E-6, E-7, E-8, and E-1], Six-Neut [neutralizing MAbs E-2, E-3, E-4, E-5, E-7, and E-1], Four-EP [epitope recognition-based MAbs E-2, E-3, E-8, and E-1], and E-1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488679&req=5

toxins-07-01854-f001: Neutralizing activity of oligoclonal combinations [16]. Different BoNT doses were pre-incubated with combinations of equally diluted MAb ascites fluids (final dilution 1:200, equals ~25 µg/mL of IgG) and then injected into mice. The results indicate the maximal toxin dose that the mice could withstand. Anti-serotype B MAb results are zoomed separately. Anti-serotype A MAb panel: Seven [A-4, A-1, A-6, A-2, A-3, A-8, A-7], Four-EP [epitope recognition recognition-based MAbs A-4, A-1, A-3, and A-8], Four-Neut [neutralizing MAbs A-4, A-1, A-6, and A-2], Three [A-4, A-1, and A-8 or A-3]. Anti-serotype B MAb panel: Seven [B-4, B-2, B-1, B-3, B-6, B-5, and B-7], Two (B-1) [B-4 and B-1], and Two (B-5) [B-4 and B-5]. Anti-serotype E MAb panel: Eight [E-2, E-3, E-4, E-5, E-6, E-7, E-8, and E-1], Six-Neut [neutralizing MAbs E-2, E-3, E-4, E-5, E-7, and E-1], Four-EP [epitope recognition-based MAbs E-2, E-3, E-8, and E-1], and E-1.
Mentions: Within each serotype-specific group, we produced neutralizing MAbs, the majority of which were protective against a toxin dose of 10 Mouse Lethal Dose 50% (MsLD50). Encouraged by these results, we sought to determine whether the MAb combinations in each serotype-specific group exhibited increased neutralizing activity. The best combination for anti-serotype E MAbs displayed a very high synergistic neutralizing activity of up to 400-fold over that of its components (Figure 1). The cocktail of anti-serotype A MAbs, which protected against 125,000 MsLD50 of toxin A, had a 154-fold improvement over the calculated additive effect of the mixture’s components.

Bottom Line: Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations.Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation.The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, Israel Institute for Biological Research, Ness Ziona 7410001, Israel. erand@iibr.gov.il.

ABSTRACT
Monoclonal antibodies (MAbs) are among the fastest-growing therapeutics and are being developed for a broad range of indications, including the neutralization of toxins, bacteria and viruses. Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations. Moreover, the efficacy of an individual neutralizing MAb may significantly be hampered by the potential absence or modification of its target epitope in a mutant or subtype of the infectious agent. These limitations of individual neutralizing MAbs can be overcome by using oligoclonal combinations of several MAbs with different specificities to the target antigen. Studies conducted in our lab and by others show that such combined MAb preparation may present substantial synergy in its potency over the calculated additive potency of its individual MAb components. Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation. In this review, the synergistic neutralization properties of combined oligoclonal Ab preparations are described. The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed.

No MeSH data available.


Related in: MedlinePlus