Improving Biologics’ Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures

Abstract

Monoclonal antibodies have revolutionized the treatment of many diseases, but their clinical efficacy remains limited in some other cases. Pre-clinical and clinical trials have shown that combinations of antibodies that bind to the same target (homo-combinations) or to different targets (hetero-combinations) to mimic the polyclonal humoral immune response improve their therapeutic effects in cancer. The approval of the trastuzumab/pertuzumab combination for breast cancer and then of the ipilimumab/nivolumab combination for melanoma opened the way to novel antibody combinations or oligoclonal antibody mixtures as more effective biologics for cancer management. We found more than 300 phase II/III clinical trials on antibody combinations, with/without chemotherapy, radiotherapy, small molecules or vaccines, in the ClinicalTrials.gov database. Such combinations enhance the biological responses and bypass the resistance mechanisms observed with antibody monotherapy. Usually, such antibody combinations are administered sequentially as separate formulations. Combined formulations have also been developed in which separately produced antibodies are mixed before administration or are produced simultaneously in a single cell line or a single batch of different cell lines as a polyclonal master cell bank. The regulation, toxicity and injection sequence of these oligoclonal antibody mixtures still need to be addressed in order to optimize their delivery and their therapeutic effects.

Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

“…Combinations of passive therapies targeting HER1 and HER2 oncogenes have arisen as an attractive alternative in cancer immunotherapy, proving to be effective in controlling tumor burden ( 21 ) and preventing the development of resistance to TKI and MAbs ( 40 , 42 ). Additional studies have suggested that mixtures of antibodies targeting non-overlapping epitopes are more efficient than single antibodies in inducing HER receptors’ downregulation ( 43 ) and inhibiting tumor progression ( 44 , 45 ).…”

“…On the other hand, MAbs-induced downregulation of the targets is counteracted by endosomal escape and recycling following endocytosis. In this regard, oligoclonal antibody cocktails have been developed to mimic polyclonal antibodies’ (PAbs) response (as induced by infection or vaccination) and to improve their therapeutic effects ( 21 ). However, this approach has the drawbacks of enhanced toxicity and limited polyclonality, which could be heightened by cancer vaccines that are characterized by a remarkable safety profile ( 22 ).…”

It is Never Too Late for a Cocktail - Development and Analytical Characterization of Fixed-dose Antibody Combinations

“…The second approach to manufacturing antibody cocktails is to co-express and simultaneously purify all mAbs as a mixture. 21,36 This approach could be susceptible to more manufacturing difficulties related to the purification and analytical characterization of the drug substance, but it becomes feasible when the antibody mixture contains many mAbs. This is the case of rozrolimupab (Symphogen), an antibody cocktail containing 25 unique mAbs produced by co-expression from a mixture of 25 CHO cell lines each expressing one of the antibodies.…”

“…For example, each mAb from a therapeutic combination can be formulated in an individual dosage form, and the individual mAbs can be mixed together prior to administration. 21 The co-administration of antibodies has to be distinguished from the sequential administration that is used in combination therapies. 21 In the sequential administration, the first mAb is administered alone, followed by the second mAb, followed by the third mAb, etc., while in co-administration the mAbs are combined directly before administration; for example, by mixing them in the same infusion bag.…”

“…Such fixed-dose combinations (FDCs) of therapeutic mAbs, casually called antibody cocktails, become increasingly popular but bring new challenges to their pharmaceutical development and analysis. [19][20][21] For example, a sound scientific explanation of the reason to combine two or more mAbs into FDCs will be required. This rationale should consider not only aspects related to the biological activity (non-overlapping epitopes, affinity, avidity, effector functions) but also safety concerns, for example, related to the immunogenicity of the individual mAbs compared to their mixture.…”