Epidermal growth factor receptor (EGFR) is a validated therapeutic target in cancer and EGFR antagonists with greater effectiveness than existing clinical agents remain of interest. Here, we report a novel approach based on Sym004, a mixture of two anti-EGFR monoclonal antibodies directed against distinct nonoverlapping epitopes in EGFR extracellular domain III. Like anti-EGFR monoclonal antibodies in current clinical use, Sym004 inhibits cancer cell growth and survival by blocking ligand-binding receptor activation and phosphorylation and downstream receptor signaling. However, unlike the other antibodies, Sym004 induces rapid and efficient removal of the receptor from the cancer cell surface by triggering EGFR internalization and degradation. Compared with reference anti-EGFR monoclonal antibodies, Sym004 exhibited more pronounced growth inhibition in vitro and superior efficacy in vivo. Together, these findings illustrate a strategy to target EGFR more effectively than existing clinical antibodies.

Abbreviations: ADA, anti-drug antibody; ADCC, antibody-dependent cellular cytotoxicity; ADME, absorption, distribution, metabolism and excretion; APC, antigen-presenting cell; AS, ankylosing spondylitis; CAPS, cropyrin-associated periodic syndromes; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CDR, complementarity-determining region; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; CRA, cytokine release assay; CrD, Crohn disease; CRS, cytokine release syndrome; CTLA-4, cytotoxic T lymphocyte antigen-4; DAMPs, damage-associated molecular patterns; DC, dendritic cell; DTH, delayed-type hypersensitivity; EBV, Epstein Barr virus; EFD-PPND, embryo-fetal development and peri-/ post-natal development; EMA, European Medicines Agency; EPAR, European Public Assessment Report; EPO, erythropoietin; ESG, Expert Scientific Group; FDA, Food and Drug Administration; FIH, first-in-human; GD, gestation day; GLP, good laboratory practice; HED, human equivalent dose; HHV-8, human herpes virus-8; HLA, human leukocyte antigen; HSA, human serum albumin; HSP, heat shock protein; HTLV-1, human T cell leukemia virus-1; ICH, International Conference on Harmonization; IHC, immunohistochemistry; KLH, keyhole limpet hemocyanin; LCV, lymphocryptovirus; LFA-1, leukocyte function antigen-1; LPS, lipopolysaccharide; mAb, monoclonal antibody; MABEL, minimum anticipated biological effect level; MHC, major histocompatibility comlex; MoA, mechanism of action; MRSD, maximum recommended starting dose; MS, multiple sclerosis; NCE, new chemical entity; NHP, non-human primate; NK, natural killer; NLR, nod-like receptor; NOAEL, no observed adverse effect level; PAD, pharmacologically-active dose; PAMPs, pathogen-associated molecular patterns; PEG-MGDF, pegylated megakaryocyte growth and development factor; PD, pharmacodynamic; PHA, phytohemaglutinin; PK, pharmacokinetic; PML, progressive multifocal leukoencephalopathy; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RMP, risk management plan; RO, receptor occupancy; RSV, respiratory syncytial virus; SBA, summary basis of approval; SLE, systemic lupus erythromatosus; SPC, summary of product characteristics; SRBC, sheep red blood cell; TCR, tissue cross reactivity; TDAR, T cell-dependent antibody response; TLR, toll-like receptor; TT, tetanus toxoid; UC, ulcerative colitis; VLA-4, very late antigen-4Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxic...

Mannan-binding protein (MBP) is a lectin which, upon binding to certain carbohydrates, activates the classical pathway of complement without the involvement of antibody or C1q. Deficiency of the MBP is associated with an opsonic defect and recurrent infections during early life. An amino acid substitution in the exon 1 at codon 54 in the MBP gene (GGC [glycine] to GAC [aspartic acid]) has been shown to be closely associated with low MBP concentration in Caucasoids. The gene frequency of the mutant allele in this population has been estimated at 0.13. In the study described here, we investigated the association between the mutant allele and MBP protein concentration in Eskimos from East-Greenland and black Africans from the Baringo District in Kenya. The frequency of the GAC allele was identical in Eskimos and Caucasoids (0.13). No overlap with regard to MBP concentration between the genotypes was found in the Eskimos. In contrast, the Africans revealed a low frequency of the GAC allele (0.009). However, the median MBP protein concentration was approximately 5 times lower among the Africans than the Eskimos. In 12.6% of the Africans and in 2.5% of the Eskimos, MBP was undetectable. Thus, MBP deficiency is the most frequent immunodeficiency so far described. The high prevalence of MBP deficiency among healthy individuals indicates that MBP deficiency also confers some selective advantages. We advance the hypothesis that MBP deficiency is maintained in populations because MBP deficiency decreases the infectivity of some intracellular micro-organisms which are dependent on opsonization.

IL-21, a member of the common γ-chain family of cytokines, has pleiotropic effects on T, B, and NK cells. We found that IL-21 and the prototype common γ-chain cytokine IL-2 can stimulate proliferation and cytokine secretion by Ag-specific rhesus monkey CD8+ T cells. However, unique among the members of this family of cytokines, we found that IL-21 drives these cells to apoptosis by down-regulation of Bcl-2. These findings suggest that IL-21 may play an important role in the contraction of CD8+ T cell responses.

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