TL;DR: An attempt to improve monoclonal antibody-based cancer therapeutics, original research just published helps to confirm our hypothesis about IgG4 and cancer progression, as well as explain the mechanisms behind hyperprogressive disease.
Any extracts used in the following article are for non-commercial research and educational purposes only and may be subject to copyright from their respective owners.
Some research is just too important to wait. It also ties in nicely with the IgG4 series.
I recommend at least reading the background introduction to antibodies, in the last Substack.
In April our review “Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression”1cleared peer review, and is available by open access:
Abstract
Repeated inoculation with messenger RNA (mRNA) vaccines elicits immunoglobulin G4 (IgG4) antibody production. Such an increase in the concentration of specific and non-specific IgG4 antibodies allows the growth of some types of cancer by blocking the activation of effector immune cells. This work proposes the hypothesis that cancer growth may be indirectly promoted by increased concentrations of non-specific IgG4 antibodies by the following mechanisms: 1) IgG4 antibodies can bind to anti-tumor IgG1 antibodies and block their interaction with receptors located on effector cells, thus preventing the destruction of cancer cells, 2) IgG4 can interact with fragment crystallizable gamma receptor IIb (FcγRIIB) inhibitory receptors, thus reducing effector functions of innate immune cells, and 3) targeting of specific epitopes by IgG4 could be oncogenic by inducing the production of a microenvironment that can promote cancer development. This article reviews the supporting literature and suggests several experimental protocols to evaluate this hypothesis in the context of repeated inoculation with mRNA vaccines. Additionally, this work proposes some management options aimed at reducing the unfavorable molecular consequences that could mediate cancer development when encountering high concentrations of IgG4 antibodies.
Figure 1. Roles of immunoglobulin G4 (IgG4) antibodies in local immune escape. Under normal conditions, the IgG1 antibody recognizes the cancer-associated antigen. IgG1 then binds through the fragment crystallizable (Fc) to its receptor, located on the natural killer (NK) cells (shown) or macrophages (not shown). These are activated and NK cells release perforins and granzymes that destroy the cancer cell while macrophages phagocytose the cancer cell. However, when present, IgG4 could bind to the Fc region of the IgG1 antibody, thus inhibiting its union with its respective receptor located on the NK or macrophage cell. As a consequence, these effector cells are not activated and therefore cannot destroy the cancer cell. Fab: antigen-binding fragment. This Figure was created using Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License
We cited research by Wang et al. from 2020: “An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy”2.
The focus of this Substack, Wang et al. just published “Fc–Fc interactions and immune inhibitory effects of IgG4: implications for anti-PD-1 immunotherapies”,3 on 25th June. The lead author is Weifeng Zhang.
We concluded our review with proposed in vitro assays and animal tests that could be undertaken to test our hypothesis. This new paper goes a long way to doing just that for all the points we proposed. Their findings are somewhat disturbing, due to the implications.
This Substack will highlight key takes from the paper.
It is important to keep researching, interpreting and posting about all pathologies linked to the LNP-mRNA health disaster. The theoretical risk is materialising as increasing rates of deaths, disabilities and hospitals that are running at or over capacity all year round. This is only going to get worse, such is the nature of progressive diseases.
If you aren’t speaking out by now you are complicit, and almost all connected parties remain largely silent, or at best just post the odd limited-hangout article.
The pharma puppet CDC (Crimes, Deaths & Cover-ups) is one exception. They are indeed speaking out, but only in the most criminally deranged way:
In the last Substack I included some alarming graphs posted by Ilkka Rauvola on 5th June showing increased annual rates of excess deaths in Finland:
From: “Finland's epidemic 5 June 2024: excess deaths for <60 year olds continue to grow. For 5-9 year olds, excess deaths are now at 2.4 times pre-pandemic level. 1/x”. Source: https://x.com/jukka235/status/1798339937303204229
As feared, this is probably being mirrored in all the highly vaccinated countries. We can now add Norway to the list. IgG4-RD will be a factor in this:
Programmed cell death protein 1 (PD-1) is a protein in humans encoded by the PDCD1 gene. It acts as a surface receptor on T and B cells. When it is working as it should as an immune checkpoint it protects against autoimmunity by promotingapoptosis (programmed cell death, hence the name) of antigen-specific T-cells in the lymph nodes and by reducingapoptosis of anti-inflammatory, immune-suppressive regulatory T-cells (Tregs).
Many cancers exploit PD-1 by expressing it, thus impeding anti-tumour immune responses.
Monoclonal antibodies using a stabilised form of IgG4 are given to cancer patients as an “immune checkpoint inhibitor”, as IgG4 is also an antibody to PD-1.
The problem oncologists have is that it doesn’t work very well for many patients for very long, and they need to use combination therapies to get any significant response. (I have views on using Medieval poisons and burning to help you return to health, but these must wait for another time.)
Zhang et al. conducted in vitro (“in glass”) and in vivo (“within the living”) studies using wildtype and humanized BALB mice to study the effects of IgG4 on different commonly administered anti-cancer monoclonal antibodies.
BALB/c are an albino mouse with a typical lifespan of 17 months for males and 20 months for females. They are ideal for studying cancer and immunology.
IgG4-induced HPD also enters the discussion. HPD is short for hyperprogressive disease, and is the technical name for turbocancer. It is very much a real disease, not a tinfoil hat conspiracy, along the lines of graphene oxide in the jabs.
Some background to GSH, or glutathione is useful too:
GSH is a peptide synthesised in the liver and is made of the amino acids glycine, cysteine, and glutamic acid. It is involved in many processes including tissue building and repair, protein synthesis and immune function. It’s a powerful antioxidant that helps protect the body from damage caused by free radicals (eg reactive oxygen species, ROS formed from peroxides), and heavy metals.
As these are associated with cancer initiation and progression you should try to avoid being GSH deficient. Acetaminophen "(Tylenol”, “Panadol” or “Paracetamol”) is a great way to deplete your GSH, just when you need it the most to fight an infection. It was the worst advice to give to anyone with a high viral load of COVID-19 or ROS-associated vaccine side-effects.456
Although GSH has good cancer-preventative properties, including protecting against DNA damage,7 once a tumour has formed it may secrete GSH to protect itself from an early death. At this stage, the presence of GSH pivots from protective to tumor-promoting. Worst still, IgG4 appears to work synergistically with GSH to further promote tumour progression.
In the context of antibodies, “Fc” refers to the fragment crystallizable region, the tail of the antibody that interacts with cell surface Fc receptors and some proteins of the complement system. It’s sometimes called the Fc fragment chain too:
IgG4 can undergo “Fab-arm exchange” (FAE), where, unlike with other Abs, it can undergo half-molecule exchange, which results in hybridized, asymmetrical, bispecific antibodies with two different antigen binding sites. This helps to promote both anti-inflammatory and pathogenic binding:
From: “Fig. 3. Fab-arm exchange is a continuous process. Under reducing conditions the two IgG half-molecules may lose the covalent connection via interchain disulphide bridges in the hinge region, as intrachain and interchain disulphide bridges exist in a dynamic equilibrium. The resulting IgG4 half-molecules dissociate and may stochastically recombine to form intact bispecific IgG4, which may again dissociate to half-molecules for the duration of reducing conditions.” Available via license: CC BY 4.0. Source: https://www.researchgate.net/publication/343630461_Update_on_IgG4-mediated_autoimmune_diseases_New_insights_and_new_family_members/figures?lo=1
As we discussed, a major drawback to using IgG4 mAbs is that they can bind and inhibit not just PD-1 but immunoglobulins such as IgG1 too, allowing the cancer to progress rapidly instead of shrinking:
From: “Fig. 4. IgG4 is immunologically inert and may dampen immune reactions. IgG4 competes for antigen binding with other antibody (sub-)classes that may exert Fc-dependent effector mechanisms, therefore effectively inhibiting antibody effector mechanisms. IgG4 is bispecific, which allows only for monovalent antigen binding, thereby preventing the formation of antibody-antigen immune complexes in solution, and the cross-linking and endocytosis of transmembrane proteins. Furthermore, IgG4 does not bind to C1q and has reduced affinity for activating FcγR, thereby preventing complement activation or immune cell mediated mechanisms such as antibody dependent cellular cytotoxicity (ADCC).” Source: https://www.sciencedirect.com/science/article/pii/S1568997220302172?via%3Dihub
Discussion
Trastuzumab: An IgG1 monoclonal antibody therapeutic. This is also an antibody to a protein that helps breast cancer cells grow quickly, HER2 (= human epidermal growth factor receptor 2, CD340 or receptor tyrosine-protein kinase erbB-2).
Rituximab: Also an IgG1 mAb.
Penpulimab: Fc-null IgG1 mAb. By “null” it means “silenced”. An engineered mutation stops the Fc region from binding to Fc gamma receptors or complement protein C1q, eliminating immune effector functions. The objective is to remove the T-cell killing antibody-dependent cellular cytotoxicity (ADCC) of the antibody, whilst retaining its PD-1 properties.8
Nivolumab: Stabilised IgG4 S228P mAb.
Tislelizumab: Fc-null IgG4 S228P-R409K mAb.
It’s great to know they administered billions of doses of an IgG4-promoting gene agent before the mAb technology was ready. Research continues apace:
From “Figure 4. Fc modifications which reduce antibody effector function and/or FcγR binding. (A) Timeline of events detailing major discoveries, techniques used to discover variants that have a silenced Fc region and when the Fc variants were first described in the literature [57,115,124,127,128,129,130,132,133,134,135,136]. Letters refer to the common notation of the introduced amino acid substitutions as discussed in the main text.” Source: “Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment”
Key takes from: “Fc–Fc interactions and immune inhibitory effects of IgG4: implications for anti-PD-1 immunotherapies”:
Both IgG4 and the stabilised mAb form of IgG4 promoted tumour growth, whereas mAbs based on IgG1 or Fc-null IgG4 did not.
Note: Our review concerns the fact that anti-Spike IgG4 is not stabilised or Fc-null, and may hybridize via Fab-arm exchange to bind other receptors, including IgG1, promoting cancer:
Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects.
These findings showed that the tumor microenvironment is conducive for the Fc–Fc interactions of IgG4 or IgG4-type mAbs. This highlights the potential impact of IgG4-mediated immunosuppressive effects in cancer immunotherapy as the abundance of IgG, IgG1, and GSH in the tumor microenvironment creates a favorable setting for the Fc–Fc interactions involves IgG4 or IgG4 S228P anti-PD-1 mAbs.
Biotin is also known as vitamin B7. Biotinylation is a labelling process that works by attaching biotin to proteins and other macromolecules. The process is rapid, specific, and generally does not disturb the structure of the molecule that it binds to.
Biotin-labeled trastuzumab (anti-HER-2 IgG1) and rituximab (anti-CD20 IgG1) showed specific binding to tumor antigens while biotin-labeled IgG1wt, IgG4wt, penpulimab, and nivolumab did not bind. Immunocytochemistry and immunofluorescence confirmed binding of IgG4wt and nivolumab to tumor cells (BT-474 and Raji) after these cell pre-incubation with trastuzumab or rituximab.
These results indicate that IgG4 antibodies interact with IgG1 antibodies on tumor cells through Fc–Fc interactions, blocking antitumor antibodies. Conversely, biotin-labeled IgG1wt and penpulimab do not exhibit comparable binding to the tumor cells (figure 3B,C).
Extracted from Figure 3 for clarity:
“The binding of IgG4wt and IgG4 S228P anti-programmed cell-death 1 monoclonal antibody to IgG1 antibodies immobilized on cancer cells. (A) Schematic representation of the immunocytochemistry and immunofluorescence experiments. The presence of HER-2 or CD20 antigens on cancer cell lines (BT-474/Raji) was confirmed using mouse anti-human antibodies. Cancer cells were fixed on slides and incubated with trastuzumab or rituximab to immobilize the antibodies. Biotin-labeled IgG4wt, IgG1wt, penpulimab, and nivolumab were tested for binding to the immobilized IgG1 on the cells.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11203076/
“(C) Similar immunofluorescence results seen with rituximab on Raji cells. Positive binding indicated by brown staining or green fluorescence. Scale bar=60 µm. Ritu, rituximab; Trastu, trastuzumab.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11203076/
They even provide a somewhat psychedelic time lapse. You may need to watch it a few times:
In ADCP experiments, a time-lapse imaging technique using multiple wells and fluorescence microscopy was employed to visually capture the dynamic process of cellular phagocytosis. The recordings documented the phagocytic activity of BT-474 cell models over a 12-hour period for each subgroup. Analysis of the results revealed that in the IgG4wt and nivolumab groups, macrophages had reduced ability to engulf tumor cells, allowing tumor cells to grow and adhere well (online supplemental video 1).
TNFα secretion was significantly inhibited by higher concentrations of IgG4. IgG4 has a stronger inhibitory effect on cytokine secretion by activated CD8+ T lymphocytes compared with other IgG subtypes. IgG4 exerts such immunosuppressive effects by binding to FcRs, and the binding reaction can be inhibited by FcR blocker (figure 5B).
We observed that both nivolumab and IgG4wt displayed comparable effects in promoting tumor growth in 4T1 breast cancer and CT26 colon cancer wildtype mouse models (figure 6B,C).
Extracted from Figure 6 for clarity:
“IgG4 proteins promote tumor growth on mouse tumor-bearing models. (A) BALB/c mice with subcutaneous tumors were randomly assigned to groups and given different treatments, including IgG1wt, IgG4wt, penpulimab, or nivolumab. The proteins were dissolved in PBS at 2 mg/mL and given at a dose of 200 µg peritumorally every 5 days for four injections. The control group received PBS. Cancer models were created by injecting 4T1 cells or CT26 cells under the left forearm after the initial protein injection. (B–C) Tumor tissues were analyzed in groups of 4T1 breast cancer (n=5/group for wild-type, n=4/group for humanized PD-1 model) and CT26 colon cancer (n=4/group) mouse models. Tumor growth curves were plotted for each treatment group in both models.”
Breast cancer: wild-type mice. PBS is the control. Pen is Fc-null IgG1 mAb. Nivo is stabilised IgG4 S228P mAb.
Colon cancer mice. PBS is the control. Pen is Fc-null IgG1 mAb. Nivo is stabilised IgG4 S228P mAb.
Breast cancer: humanized mice. PBS is the control. Pen is Fc-null IgG1 mAb. Nivo is stabilised IgG4 S228P mAb.
Nivolumab (stabilised IgG4 S228P mAb) promotes cancer in most cell lines, but IgG4wt leads in almost all cases:
This is the kind of cancer “magic bullet” you don’t want. IgG4 homes in like a Sidewinder to bind IgG1 in the tumour, potentially leading to HPD.
The synchronous abundant distribution of GSH and IgG in various cancer tissues (figure 1) suggests that IgG4 is prone to Fc–Fc interactions in the tumor microenvironment as illustrated in figure 2D.
Previously we demonstrated that IgG1 derived from tumor patients specifically binds to their own tumor tissues thereby becomes the immobilized target for IgG4 to bind to in an Fc–Fc manner.18
Effects of GSH:
The presence of GSH and immobilized IgG could also promote the Fc–Fc interactions of IgG4 S228P anti-PD-1mAbs to immobilized IgG. This interaction may hinder antitumor immune responses and promote tumor growth as we observed in the animal models (figure 6), while potentially causing off-target effects, resistance to immunotherapy, and immune evasion for IgG4-type anti-PD-1 mAbs in clinical therapy.
HPD in 6 to 43% of cancer patients on immune checkpoint inhibitors. It’s not a theoretical edge case phenomenon:
This could lead to side effects such as HPD. HPD manifests as accelerated tumor growth with poor prognosis seen in patients after immune checkpoint inhibitor therapy at an incidence ranging from 6% to 43%.16
Mutations in the tumour may lead to increased GSH production and further resistance to IgG4 checkpoint inhibitor mAbs:
Researches [sic] have linked HPD to dysregulated tumor signaling pathways34 35 and mutations in genes like KRAS, STK11/LKB1,36 37 MDM2/MDM4, and EGFR in patients on PD-1 blockade.35 These mutations were also found affecting synthesis and metabolism of GSH in tumor microenvironment, leading to increased GSH levels.37–40 Tumors that possess these mutations may exhibit resistance to IgG4 S228P anti-PD-1 mAb immunotherapy by promoting the dissociation of IgG4 and Fc–Fc interactions through increased levels of GSH.
Even without HPD, they don’t work very well for very long. This leads to recurrence, a poorer prognosis and the need to use combination therapy:
Contrary to the prevalent occurrence of HPD, the efficacy of anti-PD-1 mAb immunotherapy in diverse cancers is moderate. Only about 30% of patients exhibited favorable responses to these treatments, and even fewer experienced sustained benefits.41
Most patients ultimately face disease progression, suggesting the emergence of potential secondary resistance mechanisms.41 42 Various approaches are currently being tested to overcome these challenges, with one extensively researched strategy involving enhancing efficacy through the combination of anti-PD-1 mAb with other IgG1 mAbs.
Attempts to increase the efficacy of IgG1 mAbs can make things worse though, not better:
However, previous studies had found a higher prevalence of HPD in patients undergoing combination immunotherapy as opposed to monotherapy (15.4% vs 4.4%),43 with the proportion up to 30%.44
Can you predict how you will respond, and what combination will work for you?
While the underlying mechanisms remain unclear, the Fc–Fc interactions could be a potential contributing factor. Our cellular tests showed that choosing the IgG framework is crucial for the effectiveness and safety of combination therapies involving “anti-PD-1 mAb plus antitumor IgG1 mAb.
Administering IgG1 with IgG4 mAbs may also fail, with off-target effects:
Administrating IgG4 S228P anti-PD-1 mAb with antitumor IgG1 mAb may lead to Fc–Fc interactions, particularly in the presence of increased GSH levels in the tumor microenvironment. This can reduce the antitumor effectiveness of the IgG1 antibody and increase off-target effects of the anti-PD-1 mAb.
Fc-null IgG1 anti-PD-1 mAb could be a safer option for these combination treatments, as it avoids the detrimental Fc–Fc interaction.
MaBs appear to work better with younger patients, at an earlier cancer stage:
Nevertheless, IgG4-type anti-PD-1 mAb can still be effective in cancer treatment. In the humanized PD-1 mouse model (figure 6), nivolumab demonstrated favorable efficacy and was not significantly inferior to penpulimab. The mice were in good condition with robust immune reserves, akin to patients with early stage cancer.
It’s not exactly a strong endorsement:
Under such condition, the inhibitory effect of Fc–Fc interactions are likely to be overshadowed by the immune-promoting effect brought by PD-1 blockade, thereby slightly weakens its efficacy.
mRNA gene agents aside, who is most likely to need cancer treatments? The ones most at risk of HPD from the therapeutic:
Previous studies45 46 indicated that patients with advanced tumor stage, poor physical condition, and old age (>65 years) were prone to HPD after treatment with ani-PD-1 mAbs (typically nivolumab or pembrolizumab).
For advanced cancer patients with lower immune capacity, the beneficial effect of PD-1 blockade is limited while the immunosuppression of IgG4 anti-PD-1 mAbs Fc–Fc interactions still exists, and even is enhanced by elevated GSH.19 47
The Fc–Fc interactions may affect its efficacy and potentially lead to tumor progression in such conditions. However, due to animal welfare issues caused by excessive tumor burden, we were unable to use this model to simulate advanced tumors patients with poor physical condition."
“A patient with IgG4-RD commonly has high IgG4 levels. If vaccinated with these mRNA vaccines, their levels probably would increase even more, thus causing a higher propensity for cancer growth and aneurysms, but also other disorders.”
- Dr Alberto Rubio-Casillas
… studies10 11 18 19 48 49 have shown that IgG4 levels within the tumor microenvironment are typically higher than normal (approximately 0.5 mg/mL) and contribute to an immunosuppressive environment.
Injectable PD-1 mAbs are typically administered at doses of 200–480 mg every 2–3 weeks with terminal half-life of about 27 days.50
The cumulative presence of IgG4 mAbs from repeated injections could elevate the total IgG4 levels in the patient’s system and lead to a concentration-dependent inhibitory effects in vivo.
These effects were evident in the Fc-functional IgG4 S228P anti-PD-1 mAb, leading to the inhibition of its functional activity.
IgG4 can stop checkpoint inhibitors from preventing PD-1-induced immune suppression of CD8+ cells:
IgG4 has a high affinity to FcγRIIB, and a recent study found that FcγRIIB positive CD8+ T cells exhibited reduced responsiveness to Fc-functional anti-PD-1 mAb.
This study proposes a novel mechanism of HPD in the context of the persistent IgG4 Fc–Fc interactions observed in the traditional IgG4 S228P anti-PD-1 mAb as depicted in figure 7.
Addressing this may help to improve cancer therapeutics and reduce the risk of HPD, but will do little to reduce the IgG4 load or HPD risk of the mRNA-induced class-switched with cancer:
This additional mechanism helps to understand how immunotherapy resistance and HPD are influenced by the Fc fragment of anti-PD-1 mAb, providing insights into possible alternative mechanisms.
The Fc-null IgG1 framework appears to present several advantages in comparison to the traditional IgG4 framework for developing anti-PD-1 mAb. These advantages include the absence of Fc–Fc interactions preventing the antibody from binding to other immobilized IgG, thereby avoiding off-target effects and attenuating the immune response of antitumor antibodies.
Furthermore, the elimination of Fc:FcR interactions would prevent off-target effects and autoimmune phagocytosis injury, as well as inhibitory effects on immune cells mediated by Fc:FcR binding.
Furthermore, the Fc-null IgG1 framework exhibits a more stable structural form with improved solution stability26 and the ability to withstand higher redox stress in the tumor microenvironment.
I will break down the caption for legibility, as it’s H U G E.
The known mechanism for HPD involves IgG4 Fc:FcR binding, promoting immune-suppressive regulatory T-cells (Tregs).
The newly proposed, additional mechanism is as we discussed: Fc–Fc interactions leading to the blocking of ADCC, ADCP, and CDC effects.
ADCC: Antibody-dependent cellular cytotoxicity.“Also called antibody-dependent cell-mediated cytotoxicity, is an immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing tumor- or pathogen-derived antigens on their surface.”9
ADCP: Antibody-dependent cellular phagocytosis.“An immunological mechanism of elimination whereby tumor cells are targeted with monoclonal antibodies (mAbs) to promote their clearance from the body by phagocytic immune cells.”10
CDC:Complement-dependent cytotoxicity“is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell (e.g. bacterial or viral infected cell), the classical complement pathway is triggered by bonding protein C1q to these antibodies, resulting in formation of a membrane attack complex (MAC) and target cell lysis.”11
Initially, B cells produce bivalent IgG4 antibodies that can be exchanged to form bispecific IgG4.
In the tumor microenvironment, IgG4 can react with anticancer IgG antibodies through Fc–Fc interactions and lead to the blocking of ADCC, ADCP, and CDC effects, promoting tumor growth.
Additionally, IgG4 inhibits CD8+ T cells and natural killer cells, impeding their ability to target and eliminate tumor cells.
It also promotes M2 macrophage polarization, creating an immunosuppressive tumor environment.
The Fc-functional IgG4 S228P anti-PD-1 mAb retains Fc–Fc interactions and Fc:FcR interaction like wildtype IgG4.
In vivo, this mutated mAb may block anticancer IgG-mediated immune response through Fc–Fc interactions, promoting tumor growth.
We proposed this Fc–Fc interactions of IgG4 S228P anti-PD-1 mAb as a new and additional mechanism potentially causing hyper-progressive disease. This severe side effect has been reported in previous studies to be triggered by the Fc:FcR interaction among IgG4-type anti-PD-1 mAb and the Fc receptor of macrophages and T cells.12–15 51
Chia Tai Tianqing is described by Bloomberg as a supplier of “liver disease, cancer, cardiovascular, anti-infective, digestion, respiratory, and diabetes medicinal products. Chia Tai Tianqing Pharmaceutical Group sells its products domestically and internationally.”12
Akeso Biopharma“develops, manufactures, and distributes innovative antibody drugs. The Company manufactures and sells angiocarpy, tumour, and other innovative investigative drugs for the treatment of major diseases like cancer and autoimmune diseases. Akeso Biopharma conducts businesses worldwide.”13
Competing interests: TZ is an employee of Chia Tai Tianqing Pharmaceutical Group and YX and BL are employees of Akeso Biopharma.
Conclusion
We concluded our review with the following discussion:
The results of the Fc receptor competition studies demonstrated that a significant IgG4 concentration is necessary for competition with IgG1 in attaching to Fc receptors on macrophages and peripheral blood mononuclear cells (PBMCs) [35]. That is precisely what Irrgang et al. [8] found in their study: they observed that in a cohort of Pfizer/BioNTech vaccinees, there was a 1.4-fold increase in IgG1 total antibodies between the second and third immunization while nearly a 39-fold increase in IgG4 antibodies in same period. This clearly indicates an increase in the ratio of IgG4 to IgG1 antibodies. As repeated mRNA vaccination caused a decrease in the percentage of IgG1 antibodies relative to the percentage of IgG4 antibodies [8], the latter could contend with IgG1 in interacting with Fc receptors, thus blocking anti-cancer responses. In addition, IgG4 antibodies could interact with inhibitory Fc receptors, further attenuating the effect of IgG1 antibodies.
In science, the only way to confirm or refute a hypothesis is by performing experiments. This hypothesis may be incorrect, but it needs to be refuted experimentally. It is therefore encouraged that scientists experimentally evaluate this hypothesis. Useful information on how to perform such experiments is found in the previously discussed works [35, 54, 55] of IgG4-induced hyperprogressive disease. Several experimental protocols are proposed that could be undertaken to test this hypothesis:
From “Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression“ (2024)
Although the excellent research by Zhang et al. did not specifically use anti-Spike IgG4 mAbs it does lend further strong experimental support for our hypothesis.
Alarmingly, they also provide further experimental evidence to support the hypothesis that IgG4 can lead to hyperprogressive disease (“turbocancer”), through multiple Fc to FcR interactions.
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“T cell binding antigen, illustration. T lymphocytes, or T cells, are a type of white blood cell and components of the body's immune system. They recognise a specific site (antigen) on the surface of pathogens or foreign objects, bind to it, and attract antibodies or cells to eliminate that antigen.” Royalty Free. Credit KEITH CHAMBERS / SCIENCE PHOTO LIBRARY
Raszek M, Cowley D, Redwan EM, Uversky VN, Rubio-Casillas A. Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression.Explor Immunol. 2024;4(2):267-284. doi:10.37349/ei.2024.00140
Wang H, Xu Q, Zhao C, et al. An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy. J Immunother Cancer. 2020;8(2):e000661. doi:10.1136/jitc-2020-000661
Koufoglou E, Kourlaba G, Michos A. Effect of prophylactic administration of antipyretics on the immune response to pneumococcal conjugate vaccines in children: a systematic review.Pneumonia (Nathan). 2021;13(1):7. doi:10.1186/s41479-021-00085-8
Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I. Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies.American Journal of Epidemiology. 2018;187(8):1817-1827. doi:10.1093/aje/kwy086
Sáez GT, Valls V, Muñiz P, et al. The role of glutathione in protection against DNA damage induced by rifamycin SV and copper(II) ions.Free Radic Res Commun. 1993;19(2):81-92. doi:10.3109/10715769309056502
Kang CE, Lee S, Ahn T, et al. Antibody-dependent cellular cytotoxicity-null effector developed using mammalian and plant GlycoDelete platform.Sci Rep. 2022;12(1):19030. doi:10.1038/s41598-022-23311-9
Cyprinus Carpio, another not very good but excellent tour de force, as you are more persistent than a pathogen or toxin mistaken for an allergen. In the case of the latter tolerance via IGG4, although subtle, usually is quite fatal. But they knew long ago and all along, that very fact would make their repurposed gene therapy, quite "safe" and oh so very effective Mr Mulder.
Thank you so much for posting. I plowed through, struggling with terminology, concepts, and diagrams. Certainly I would fail the quiz, but my reward in the middle of Jefferson Airplane and the sidewinder missile was priceless.
Cyprinus Carpio, another not very good but excellent tour de force, as you are more persistent than a pathogen or toxin mistaken for an allergen. In the case of the latter tolerance via IGG4, although subtle, usually is quite fatal. But they knew long ago and all along, that very fact would make their repurposed gene therapy, quite "safe" and oh so very effective Mr Mulder.
Thank you so much for posting. I plowed through, struggling with terminology, concepts, and diagrams. Certainly I would fail the quiz, but my reward in the middle of Jefferson Airplane and the sidewinder missile was priceless.