Monoclonal Antibodies in ICU Management of Sepsis, Matters of Affinity, Targeting and Specificity

Acute primary severe infection, sepsis caused by an aggressive pathogen usually carries the features of a robust inflammatory immune response. Later exhaustion and retrieval takes solace, creating an environment of aggravated susceptibility. Acute sepsis, due to a sovereign critical illness is immunologically explainable by the emergence of jeopardy created due to an already engaged inflammatory reaction elicited by the primary trigger, in which the requirement of multitasking and dividing forces weakens defense. It is how simple colonization, or even mere presence in a terrain abundant in opportunists leads to manifest infection by pathogens that are flexible in developing evasion mechanisms for survival. The global incidence of sepsis in 2017 was 48,9 million with an overall mortality of 19.7%, and 46,6% of deaths were as a consequence of non-infectious causes [1]. Over 84% of deaths occurred in countries with nonhigh SDI (sustainable development index). More than 50% of ICU deaths are due to sepsis and septic complications.

Polyclonal antibodies

Polyclonal antibodies had been tested in sepsis management with non-consistent results for decades. We occasionally reach for them in severe, refractory conditions. The reasons behind failure may be several. The 2021 Sepsis guideline recommendation places the role of polyclonal antibody application in the category of weak recommendations against use, with low quality of evidence [2]. The reasoning behind the articulation had been the large potential for bias [3], the lack of high-quality, multicenter studies, and the unfavorable cost-benefit ratio [4].

Currently used polyclonal antibodies are produced by technologies [5] requiring a large pool of donors for extraction, one unit of IVIG is conceived from thousands of donors. Consequently, even though in small concentrations, antibodies with a broad repertoire of targets, based on donor exposure, will become available, that is a leverage in primary antibody and immune deficiencies to prepare the individual for the versatility of environmental exposures. In the USA for example 13,6 million blood donations are offered yearly, while severe sepsis incidence is above half a million, hence the human pool to provide sepsis patients using the lowest dosage and single application would be sufficient for 0.3% of septic patients. IVIG (intravenous immunoglobulin) treatment thereby is not solely a matter of finances, but comes down to the plasma pool and the extensive, cumbersome production procedure. It is not primarily a cost and benefit dilemma, but a practicability and effect dilemma, with a low degree of potentiation in antimicrobial clearance due to low affinity. During the procedure, meticulous effort is directed towards virus screening and deactivation, and elimination of coagulation factors. Presently available, IVIG has a priority for indications established by convention.

An innovation in polyclonal antibody production is the enrichment of IVIG preparation with IgA and IgM [6]. IgM is a pentamer - except for the surface of B cells, whereas monomer binds antigen. The combination therapy was particularly efficient in patients who had low IgM levels during severe CAP (community acquired pneumonia). IgM is excellent in fixing complement, it has capacity to binding up to 10 antigens per molecule, and is emerging among the first antibodies during immune response as early as two days after the emergence of infection. The half-life of IgM is five days as opposed to 23 days for IgG. Studies demonstrated a decrease in CRP and PCT upon IVIG or enriched IVIG treatment [7].

Monoclonal antibody design

MAB application mimics the logic of the natural adaptive immune response in its recall phase with enhancement in specificity and affinity towards antigen. The first therapeutic monoclonal antibody antiCD 3- had been approved in 1986 in the USA for kidney transplant rejection [8].

Monoclonal antibodies are produced by a single B cell clone, targeting a unique, immunodominant antigen epitope of the pathogen. The application of therapeutic monoclonal antibodies witnessed an upstroke during the past decades. Treatment of autoimmune conditions, allergies, and biological therapy of oncological disorders gained prioritized attention. and lately neutralizing antiviral, to a lesser extent antibacterial monoclonal antibodies have been developed.

Monoclonal antibody production and utilization were recognized by the Nobel prize in 1975 for George Kohler and Cesar Milstein. Currently, more than 117 MABs of diverse specificity have been approved for human medicine by the FDA [9]. Monoclonal antibody-producing B cells are attainable from inoculated mice. The technology experienced sophistication by producing chimerichuman/ mouse antibodies, using phage libraries or humanized transgenic mice to decrease immunogenicity [10]. Another way of obtaining MABs is from infected or convalescent patients. For HIV for example, from a long-term HIV controller, the efficient broadly neutralizing MAB / VRC01 antibody to ENv C4bs had been isolated and cloned [11].

The antibody showed 75% prevention efficacy in clinical trials when administered every 8 weeks of ten infusions, in total with 30% breadth and potency. Currently, antibody combination trials are planned to further enhance preventive and therapeutic potency. During the hybridoma technology, an antibody-producing B cell clone is fused with an immortal myeloma cell line and from culture supernatants of monoclonal, usually IgG1 antibodies having superior ability in complement mediated killing, are precipitated. It is a high-cost, precision medicine momentarily, but price is a relative entity subordinate to value. Additionally, further modifications to antibody structure may be required, to enhance or limit reactivity, to prolong lifespan. The Fab portion of the antibody mediates neutralization, and opsonization, while the Fc portion mediates cell attachment, phagocytosis, signaling and processing. Due to Fc-mediated action further inflammatory response may be elicited, which in an already hyperinflammatory environment may be deleterious. Various mutations and deletions can be introduced to the Fc portion to eliminate or in contrast further enhance such adjuvant effect. As discussed later, the Fc portion may mediate ADE (Antibody-mediated Disease Enhancement), when the pathogen is carried to the cell without further capacity to eliminate, or by inducing a cytokine storm.

Monoclonal antibodies function

MABs implement many mechanisms against pathogens [12], such as blocking entry (malaria, COVID-19), neutralizing bacterial toxins, such as bezlotoxumab against Clostridium difficile enterotoxin inhibiting virulence factors, or targeting biofilms [13]. Bezlotuxumab - a fully human monoclonal antibody against toxin B of Clostridium difficile - had been tested in large clinical trials Modify I and II. A single dose of bezlotuxumab 10mg/kg iv has been proven to be effective to protect against recurrence of Clostridium difficile infection, which led to its inclusion to guidelines [14,15].

During viral infections, naturally arising neutralizing monoclonal antibodies stop viral entry and non-neutralizing antibodies utilize assorted extra- and intracellular routes to inhibit the process of viral survival [16]. The extracellular mechanisms often involve Fc receptor-mediated processes. Examples are ADCC when IgG engagement via CD16 on NK cells and granulocytes leads to cytotoxic granule release and apoptosis of the infected cell. It is how maternal ADCC inducing antibodies protect against disseminated CMV (Cytomegalovirus) or HSV (Herpes Simplex Virus) infection of the newborn. MAB production is directed toward immunodominant epitopes of viral antigens responsible for attachment and entry. Often these epitopes undergo extensive drifting, they are very plastic to promote viral evasion. If the antibody is directed towards a more conserved region, the potency does not necessarily have to be compromised and clinical efficacy is not subject to seasonal mutations. If the antibody is bound to a conserved region, neutralization may potentially still proceed. Viruses may escape monoclonal antibodies by selecting or even inducing new variants, somewhat similar to resistant bacteria selection towards antibiotics [17].

Phagocytosis

Significantly, monoclonal antibodies are instrumental in mediating and enhancing the phagocytosis of pathogens and debris. The feature was discovered by Metchnikoff and awarded the Nobel Prize in 1908. It was so huge, that the simultaneous equally important observation by Bail, that microbes are not passive participants, but active fighters and evaders in the process [18] had been barely noticed at the time. The bacteria have to be phagocytized, and directed to lysosomes for degradation, a process enhanced by the Fc portion of antibodies.

The process of engulfment, processing and presentation of microbes is accompanied by variable levels of inflammatory response [19]. Phagocytosis is initiated by opsogenic and nonopsogenic receptors. Non-opsogenic receptors recognize direct molecular patterns and mediate signaling, such as TLR receptors, and or phagocytosis, among them are C-type lectins and scavenger receptors. Some of these non-opsonic receptors participate in phagocytosis, while others prime the cells to become phagocytic. The opsonic receptors act through Fc receptors and complement molecules [20] and bind to the Fc portion of IgG or IgA molecules, and complement receptors bind to complement molecules opsonizing the pathogen. CR3(CD11b) is the most potent among complement receptors and its function is enhanced by FcIIIb. CR1(CD35) is an important contributor to phagocytosis, shown in vitro using C3bcoated E coli exposed to neutrophils, when confocal microscopy depicted the ingestion of bacteria, chemiluminescence revealed dose-dependent ROS (Reactive Oxygen Species) production, similar in its extent to the ingestion by serum-opsonized bacteria [21]. I have previously described CR1’s role in phagocytosis and wider immune regulation [22]. Several pathogens evolved mechanisms to overcome phagocytosis by resisting engulfment or securing survival intracellularly. The gram-negative multiresistant Klebsiella pneumonae uses evasion mechanisms for complement recognition, phagocytosis and MAC mediated lysis, by creating a physical barrier of the thick and sturdy capsule, by elongation and modification of LPS (Lipopolysaccharide) chain of the outer membrane [23]. Staphylococcus aureus acts via staphopain B, which cleaves CD11b from the surface of neutrophils [24]. MRSA (Methicillin Resistant Staphylococcus Aureus) US300 strain upon ingestion induces hemolysin pore-forming activity with rapid neutrophil killing. Opioids inhibit phagocytic mechanisms, this effect is particularly discernible in chronic drug abusers [25].

Monoclonal antibody function in phagocytosis

Legionella [26] species are facultative intracellular bacteria, with sensitivity to macrolides and fluoroquinons. The outer membrane protein, the immunodominant surface antigen, PAL (Peptidoglycan-Associated Lipoprotein) mediating its pathogenesis, can be targeted using monoclonal antibodies. The facultative intracellular nature of Legionella survival is achieved by creating a protective vacuole, preventing phagosomal fusion for processing. An antibody-enhancing phagocytosis might be a counterproductive measure for an intracellular pathogen, in the contrary PAL neutralizing antibodies could enhance bacterial elimination. The PAL protein is very conserved among species, and shares 100% identity within the species and 71.2% identity with the genus. There is no antibody specificity towards other bacterial species, except for Staphylococcus aureus. Hybrid neutralizing rat MABs had been produced with excellent binding to legionella strains, a sophistication of the idea to produce humanized antibodies could have a great therapeutic potential [27].

Treatment of mice with hybridoma-engineered IgG1 antibodies to immunodominant epitopes of Acinetobacter baumanii led to a significant reduction in bacterial burden and greatly improved survival of infected mice [28].

Monoclonal antibodies providing intracellular carriership for antibiotics have been produced and experimentally tested in mouse models and human Staphylococcus aureus infection. Staphylococcus can survive in professional phagocytes, and in endothelial and epithelial cells, by resisting phagolysosomal degradation. This mechanism provides support for long-term survival and metastatic spread of bacteria and resistance to antibiotics that were in vitro proven to be effective. The facultative intracellular persistence of golden staph is clinically marginally known and perhaps unreasonably underestimated. Monoclonal antibodies had been linked to rifampicin for intracellular carriership with greatly improved antibiotic efficacy in killing intracellular staphylococci [29]. Once the pathogen is coated with antibody antibiotic conjugate, it carries the drug to nonprofessional phagocytes and via Fc receptors to neutrophils and macrophages.

Antibody dependent disease enhancement

As a side effect, monoclonal antibody disease enhancement has been described in several antibody viral infection scenarios, such as dengue fever, RSV and HIV infection [30]. ADE is mediated by the Fc portion of the IgG molecule, which upon binding to cellular receptors triggers an inflammatory response and worsens the clinical picture, or when the pathogen is introduced to the cell, that is unable to provide killing. Fcgamma receptor subtypes /I, IIa,b,c, IIIa,b/ are abundantly expressed on myeloid cells but can be only activated in the presence of pathogen, FcγRI by singular IgG, all the rest only by crosslinked IgG. Activation ultimately leads to the phagocytosis of immune complexes, receptor internalization, and proinflammatory phenotype triggering that is counterbalanced by the inhibitory FcγRIIb. Upon activation in granulocytes, NADPH dependent oxidative burst is stimulated, which has antimicrobial and cytotoxic activity, and antimicrobial elements are secreted. Engagement of FcγΙIIa receptors on NK cells triggers ADCC. Fc receptors participate in endosomal processing and MHC presentation. In vitro studies can rarely fully mimic the in vivo receptor complexity, the ADE (Antibody Disease Enhancing) function of monoclonal antibodies is difficult to recognize preclinically. ADE can be prevented by truncating antibodies of their Fc region.

Sepsis

The phagocytic capability of septic patients is often impaired in comparison to ICU nonseptic patient population and negatively correlates with survival [31]. High cholesterol may impair Fc and complement receptor aggregation and enhancement of phagocytosis [32]. Iron deficiency may impair bacterial killing by inhibiting MPO (Myeloperoxidase) activity.

There is an ongoing endeavor to map the immune phenotype of sepsis. The pro-inflammatory nature of sepsis may gradually subside by inducing immunosuppression [33]. An overt and aberrant systemic inflammatory response later concludes in immunosuppression [34] due to mechanisms such as conventional dendritic cell inhibition. The role of cDCs (Conventional Dendritic Cells) is to contribute directly or as intermediates to antigen presentation, NK cell activation, and antibody production. Upon experimental CpG oligodeoxynucleotide induction of sepsis, cDC turnover of normal 3 days wasn’t impaired, but the subsequent cDCs arising from BM (Bone Marrow) and exposed to spleen SIRS were paralyzed and ovalbumin epitope presentation remained obnubilated for 21 days. Moreover, anti - OVA CD8 cytotoxic T cell production and crossreactive anti-HSV CD8 T cell activation had been impaired by Systemic Inflammatory Response Syndrome (SIRS). A similar effect was elicited upon LPS-induced SIRS, even though with different cytokine profiles, predominant IFNγ production in the CPG model and, a more enhanced IL-6, TNFα, and IFNγ production in the induced SIRS model, reminiscent of TLR9 and TLR4 activations, respectively [35].

Importantly, for immune paralysis to occur, a certain heightened SIRS must take place, which is dose-dependent on the adjuvant. Paralyzed cDCs demonstrate defective phagocytosis. A localized, organ-specific DC paralysis did not affect distant splenic dendritic cell function. This proof of concept study illuminates the logic behind differential approaches in immune modulations in early hyperactive and subsequent paralyzed stages of sepsis. Sepsis immunoparalysis and the probability of sepsis development itself in trauma patients, unfolding of septic acute kidney injury [36] was associated with truncated HLA-DR levels in prospective observational studies [37], with the likelihood of impaired antibody production due to disrupted antigen presentation.

Checkpoint inhibitors

Hence immune dysregulation is depictable from early stages and may become dominant gradually, characterized by lymphopenia, aggravated T cell apoptosis [38] and T-cell exhaustion. T cells acquire an exhausted phenotype reminiscent of a tumor environment, with high co-inhibitory molecule levels, mainly PD-1 and CTLA- 4. Monoclonal antibody treatment, particularly concomitantly against PD-1 and CTLA-4 had achieved success in malignant tumor therapies [39]. An interesting target for checkpoint inhibitor blockade is fungal sepsis, a vastly opportunistic phenotype in the exhausted host. Anti CTLA-4 and anti PD-1 inhibitors had been tested in a mouse model of Candida albicans-induced bloodstream infection as demonstrated in a two-hit, CPL (Caecal Puncture, Ligation), and Candida albicans sepsis mouse model [40].

During immuno-paralyzed stages of sepsis modulation of adaptive checkpoint inhibitors, like anti-PD-1L therapy, had beneficial effects in humans [41]. Blunt checkpoint inhibitory molecule modification however, leads to overall T cell activation, suggesting a nonspecifically enhanced T cell response with potential caveats, such as aggravated SIRS and triggering organ-specific autoimmunity. One of the most important defense mechanisms is complement-dependent, NK and phagocyte mediated pathogen elimination. Often, particularly when pathogen killing occurs intracellularly, there is a great deal of host tissue destruction by collateral damage. Genomic analysis of host response in sepsis showed differential modulation in pathways of apoptosis, necrosis, phagocytosis and cytotoxicity [42]. Neutralizing monoclonal antibodies may not be fully protective once downstream events of destruction have been initiated.

Timely and effective sepsis management includes pathogen elimination and coordination of the immune response to limit its self-destructive potential such as energy deprivation, tissue destruction and immune suppression. Few monoclonal antibodies were experimentally tested in sepsis, with results that are either negative or non conclusive. These attempts targeted modifying the immune response elements or towards the pathogen itself. Among experimentally tested immune modulations, TLR4 [43,44] inhibition had been studied on animal models of polymicrobial sepsis, when applied during the initial hyperinflammatory phase. TLR4 is a proximal contender pattern recognition receptor with unique ability to recognize LPS, the hallmark endotoxin of gram negative sepsis and tissue damage signals, such as HSP (Heat Shock Protein), HMGB1 (High Mobility Group Box 1). During the recent Covid pandemic, IL-6 inhibition in the “cytokine storm” phase had been recommended in severe cases with marginal effect, often without measuring actual IL-6 levels [45].

While monoclonal antibodies represent a highly specific targeted therapy in a concentrated form, pathogens usually display an array of pathogenic epitopes, which may become available gradually, upon entry, attachment or processing. Ultimately a cocktail of antibodies, mimicking the physiological immune response may be desirable, even though mutual antibody neutralization may occur during co-administration. Once an explicit pathogen is known, which is infrequently the case initially, the application of monoclonal antibody cocktails to support antibiotic action could be an advantageous approach.

Severe sepsis in an ICU admitted patient typically is accompanied by multiorgan dysfunction due to systemic inflammatory response, to pathogens virulence, collateral damage, and frequently ischaemiareperfusion injury [46] complicates the matter. Sepsis induces collateral damage that materializes in energy deprivation, in tissue destruction, multiorgan dysfunction and severe wasting. When analyzing sepsis itself, there is a capricious extent and distinctiveness of the inflammatory response and the pathogen burden itself presents customarily. While monoclonal antibody application and immune modulation targeting inflammation, ischaemia-reperfusion and the pathogen itself is a futuristic vision, the need to further develop the subject is underscored by mortality, morbidity, long term frailty and ultimate disability of patients. Numerous animal studies attempt to contemplate specific organ, pathogen and immune - defined scenarios, both the pathogenesis and potential modifications.

Unfortunately, there is a wide chasm between animal and clinical human research. Animal studies create a backbone to our understanding, but direct interpretation is not possible for reasons such as species differences, lack of comprehensive approach in basic animal studies, that is within one experiment it is cumbersome to targeting the many issues a clinician would be interested is, such as side effects, influence on miscellaneous organs and clinical scenarios with multitudinous insults, variables. Randomized clinical trials may carry intrinsic shortcomings, such as lack of depth, despite the large-scale approach [47].

Development of monoclonal antibodies is a highly sophisticated biochemical procedure, with numerous caveats, ultimately reflected in costly treatment. Comprehensive immune monitoring on the level of individual patient should accompany the introduction of new antibodies. Broadly neutralizing antibodies in this respect are preferential for their potential to resist mutations in receptor binding domains of pathogens. Once the pathogen enters cells, particularly in case of intracellular pathogens, monoclonal antibodies may not be sufficiently effective any longer. Anyhow, when assisting ADCC, host cells are inevitably the target. Methods, established on drug or ligand carriership for intracellular therapeutic function could represent a viable alternative. When planning for antiviral or antibacterial monoclonal antibodies, the potential for ADE can be limited with design. Majority of ICU septic patients suffer from defects in phagocytic capacity. Monoclonal antibodies are either designed against pathogens or to influence the immune response, or both, preferably in a controlled manner. Their strength is specificity, affinity and potency. The lifespan of MABs, that is modifiable to some level, is important in timing and indications of prevention or treatment. Monoclonal antibodies may represent an adjunctive modality to rational therapies, and their effect should be evaluated in such fashion. Before application intensivists should be familiar with the basic concepts in applied immunology [48].

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