TECHNOLOGY EXPLAINER
Immune Checkpoint Inhibitors
— One amino-acid residue in an antibody, and the enzyme behind a subcutaneous formulation
Immune checkpoint in torRemove "brakes" on T cells with antibodyMedicine There are two highlights in the eyes of the material. OneDesign of antibodies that re one residue or sugar chain of hingesHome Another thing is to transfer from drip to subcutaneous injectionConsolidation of high concentrations and enzymes that temporarily decompose solventsComment
- What is immunocheckpoint in tor? (3 lines)
- Two Brakes - CTLA-4 and PD-1
- Design of approved antibody - IgG1, IgG4, Fc modification
- Perspective of material ians 1:1 residue and one sugar chain changes the character of antibody
- Biomarkers - Decide the target by inspection
- ―ation - CTLA-4 antibody and ADC
- Subcutaneous Infusion – Put the Alronidase in the same vial
- How many times the concentration is, how many mL is put in a minute?
- Material Technician Perspective 2: Consisting of High Concentration Protein and Enzyme
- Approval status (reco zed by regulatory authorities)
- Glossary/Reference Materials/Reference Table
Facts= Contents described in the publication material (with source link)
The calculation of this paper= The value calculated based on the specified premise
Undetermined / Future= Items that have not been confirmed as a plan and goal
In addition to this, reading on structure arrangement, material and formulation design is"Description"is distinguished.
About this articleExplanation of antibody design and formulation technologyHome not to evaluate the effects and safety of the treatment, No medical advice. not to recommend certain medicines or treatments, or to inferior medicines, It does not tell which drip or subcutaneous injection is good. description of dosage time and concentrationcitation of attachments to determine formulation designComment General antibody (manufacturing and refining in structures and CHO cells) is handled in detail in this series "antibody medicine and ADC".
1. What is immunocheckpoint in tor? (3 lines)
- What to do:Nobel Prize for Physiology and Medicine in 2018“Discovering Cancer Treatment by Inhibiting Negative Control of Immunity”2 people“The various strategies that in、t immune system brakes have shown that they can be used to treat cancer.”ExplainFacts
- What's done:All approved productsMono nal AntibodyHome For example, nivolumab is attached“IgG4 current immunoglobulin”, “146ulation molecular weight 146 kDa”, “Recombinant Chinese Hamster Ovarian (CHO) cell strain”Facts
- What’s working now:To products that were only drip static pouring,Subcutaneous formulation containing arronidaseContact Us On September 12, 2024, the FDA approves the subcutaneous formulation of pembrolizumab on September 12, 2024, December 27, 2024, September 19, 2025Facts
The focus of materials and preparations in this field is shifting from the antibody itself to the concentration and the companion in the container. Pembrolizumab drip preparation25 mg per mLSubcutaneous Injection2.4 mL to 395 mgContact UsAbout 165 mg/mLHomeApprox. 6.6 timesThe calculation of this paperHome and subcutaneous preparationEnzymes that temporarily decompose the secretion of subcutaneous tissueis in the same vialFacts。
2. Two Brakes - CTLA-4 and PD-1
Presentation of the immune system"Accel and Brake"Here is the equilibrium.This complex balance of accelerator and brake is essential for strict control. It guarantees that the immune system is fully involved in attacking external microorganisms, while avoiding excessive activation that can lead to autoimmune destruction of healthy cells and tissues.Facts
CTLA-4：Allison studied T-cell protein CTLA-4 at University of California Berkeley in the 1990s,"CTLA-4 acts as a brake of T cells"I was one of the researchers who observed it. He has already developed antibodies that bind to CTLA-4 and block its function,The first experiment in 1994has been doneFacts。
PD-1：“In 1992, he discovered another protein PD-1 that appears on the surface of T cells several years ago.”Home Through years of experiments at Kyoto UniversityPD-1 acts as a brake of T cells as well as CTLA-4, but works in different waysShownFacts。
The abstract of two original papers is also explained.
- PD-1 (Ishida et al 1992, EMBO J）：Subtractive hybridization from cell strains that cause program cell death"PD-1 gene, a new member of the immunoglobulin gene super family"IsolatedFactsHome "PD" of the name comes from this background (programmed death)
- CTLA-4 (Leach et al 1996, Science）：“The in vivo administration of antibodies to CTLA-4 causes tumor rejection including already established tumors.”HOMECTLA-4 suppression can enable effective immune response to tumor cells and can be strengthened.ConFacts(Mouse experiment)
The action mechanism of the attachment corresponds to this figureFacts。
- Iguamumab:CTLA-4 is a negative modulation factor for T-cell activity. Iguamumab is a monoclonal antibody that binds to CTLA-4 and blocks its ligand CD80/CD86 interactions.
- Nivolumab:When PD-1 ligand PD-L1 and PD-L2 are combined into the PD-1 receptor on T cells, the growth of T cells and the production of cytokines are suppressed. PD-1 ligand expression occurs in some tumors.
- Athesolizmab:"Bond to PD-L1 and block both interactions with PD-1 and B7.1 receptors"Home More“No antibody-dependent cell injury”It is described to the antitumor immune response
Nobel FoundationSimilar to other cancer treatments, side effects can be seen and life threatening. “It is caused by autoimmune reactions due to excessive immune response”FactsHome Attachments for each productImmune intervention side effectswarnings and notes aboutFacts。 This article does not evaluate or deal with side effects.
3. Design of approved antibody - IgG1, IgG4, Fc modification
In the same "checkpoint inhibition"Subclass (IgG1 or IgG4)HomeFc part modificationis different for each product. the attachment.
| Product | Type of antibodies | Weight | First Approval (FDA) | |
|---|---|---|---|---|
| YERVOY (Iguamumab) | CTLA-4 | Recombinant IgG1 Current Immune GlobulinHome Produced by CHO cell culture | 148 kDa | March 25, 2011 （BLA 125377） |
| OPDIVO (Nivolumab) | PD-1 | IgG4 Current Immune Globulin(Human IgG4). Expressed by recombinant CHO cell stock | 146 kDa | December 22, 2014 （BLA 125554） |
| KEYTRUDA (Pembrorismab) | PD-1 | Humanized Mono nal IgG4 Current AntibodyHome Produced by recombinant CHO cells | about 149 kDa | September 4, 2014 （BLA 125514） |
| TECENTRIQ ()) | PD-L1 | Fc modified, humanized, non-saccharide-added IgG1-current immunoglobulin | 145 kDa | May 18, 2016 （BLA 761034） |
Antibody type and weight are dependent on each attachment [Reference Material 4, 6, 8, 10] and the approval date is based on Drugs@FDA [Reference Material 12]FactsHome KEYTRUDA attachments have some efficacyQuick approvalThere is a description of the fact that it is based onFacts。
4. Perspective of material ians 1:1 residue and one sugar chain change the character of antibody
IgG4 has interesting properties when you look at material chemistry. Vidarsson et al is the central part of the IgG4 hingeCPSCIgG1CPPCCompare "Intra-chain difide bonds are more easily formed between 226 and 229 cysteines."HOME "Ha)」 child that is not connected by shared bonds (one H-chain and one L-chain)"When observedFacts。
And this half child is replaced. "In vivo, IgG4 halves randomly bind to other IgG4 halves and combine two IgG4 specificities."DutchFab-arm replacementHome "Controlled by oxidation reduction conditions"Contact UsFactsHome More“IgG4’s S228P variants with IgG1 core hinges don’t form half a child.”CommentFacts。
Application materials published by PMDA (pro、 by Ono Pharmaceutical Industry) for Nivolumab "It is a genetically modified human IgG4 mono、nal antibody, and the H-chain 221th amino acid residue is replaced by Pro."and Sugar protein composed of 2 H-chains consisting of 440 amino acid residues and 2 L-chains consisting of 214 amino acid residues (Mole Weight: Approx. 145,000)FactsHome (Number of residual numbers depends on the literature.) The "221th" and "S228" of Vidarsson are not confirmed from the materials referred to in this article. )
This is a design that “stops the exchange reaction of dynamic sharing bonds to one place of the skeleton” if it is in the word of the material(This article) Di phide replacement with self-repair materials and bitrimersIntentionally usedReaction Antibody"The product is replaced by another molecule in the body, and the replacement is enclosed.Home Approx. 1,300 residues (440×2+214×2=1,308 residuesThe calculation of this paper)One of the same places in two H chains"This means that the behavior of the changes only by changing the vibration.
atezorismab in attachment"Fc modification, humanization, non-saccharide chain addition type IgG1"and The mechanism of action“No antibody-dependent cell injury”About UsFacts。
In this series "Antibody Medicine and ADC""Binding to specific Fc receptors with or without one course.I saw it. In checkpoint inhibition, the purpose is"Blinding binding"not to break the targeted cells. PD-L1 is not only a tumor cell but also an immune cell that is invasive in the tumor.FactsHome SoThere is a choice to design the Fc's work in the direction of "distinguish" rather than "foot".Dutch The same antibody skeleton depending on the applicationReversing whether to enable or remove static modificationThis is similar to the design of surface treatment.
In the manufacturing process,The design without sugar chain reduces the unevenness of the sugar chainIt is thought to work in the direction( This article explains. Please note that the handling of sugar chains in the production management is not confirmed directly to the primary information referred to in this article.
5. Biomarker - Decide the target by inspection
Many of the efficacy and effects of checkpoint in tor attachmentsFDA approved inspectionIt is written with condition. Three types of metrics used for judgment are picked up from the attachment of the emb .Facts。
| Index | What to measure | Example of attachment |
|---|---|---|
| PD-L1 expression | PD-L1 protein in tumor tissue (immune tissue chemistry staining) | [Combined Positive Score(CPS) ≥1] Tumor Expressing PD-L1 Determined by the FDA TestHome Clinical Trials PD-L1 IHC 22C3 pharmDx TPS ≥1% |
| MSI-H／dMMR | "Microsatellite instability, missing mismatch repair." | "Solid cancer of high-fr)ency microsa)ite instability (MSI-H) or mismatch repair defect (dMMR), which is determined by the FDA-approved examination" |
| TMB-H | Tumor gene mutations | "Chemical cancer of unresectable or metastatic tumor gene mutations (TMB-H) [≥10 mutations/megabase] determined by the FDA-approved test" |
AllFacts(KEYTRUDA attachment [Reference Material 6]) Both of them are part of the effect and effect.does not show all of the conditions of the target patient。
PD-L1Immunochemistry stainingPD-L1 IHC 22C3 pharmDxFactsHome In other wordsAntibody reagents, chromosomes, and standardized procedures for dyeing tissue separately from antibody of the eutic drugsHowever, it is part of how to use the product.Color roducibility and counting standardscan affect the results— This is the same composition that the variation near the threshold is divided by the inspection standard of the material. (For the composition and production of test reagents, the primary information referenced in this article is not confirmed. )
6. ation – CTLA-4 antibody and ADC
Checkpoint in torsUsed in combination with other drugsIt is also characteristic that there are many efficacy. Two combinations of materials and modalities are given from attachments.
(1) Disconnect two brakes simultaneously: PD-1 antibody and CTLA-4 antibody
The attachment of Nivolumab is a paragraph of the mechanism of action,Inhibition by combination of Nivolumab (anti-PD-1) and Iguamumab (anti-CTLA-4)Contact Us "In mouse-like tumor models, antitumor activity increased by double blocking of PD-1 and CTLA-4"FactsHome Chapter 2Judgment or higher with the threshold value such as '≥1' and '≥10'.It is a combination that removes both.
(2) Use with antibody drug complex (ADC)
Attachments for Pembrolizumab include:Effectiveness combined with ADCThere are multipleFacts。
- Rotation with Enhortsumaboidin:Treatment of adult patients with local or metastatic urinary tract epithelial cancerHome In addition to the attachment of Enhorts Mabugradin (PADCEV),Medicated with Blombrolizumab or Blombrizumab and Bellahi Arronidase AlphaThe efficacy of preoperative and postoperative treatment of myocardial invasive b der cancer is described.Facts
- Used with Sazumab Govitecan:"The primary treatment of adult patients with unresectable local progression or metastatic triple negative milk cancer"Facts
The structure of ADC (antibody, linker, payload) is handled in detail in this series.
This combination isThe same skeleton of antibody is used for completely reverse purposeRead as an example.
- ADC Antibody:Target to cells,insideDelivering Cell Injury Drugs
- Checkpoint in tor antibody:JoinBlock interactionsthe purpose of "shielding material". There is also a design that can not have Fc working to break cells like AthesolizumabFacts
In the same ‘IgG’, it becomes a completely different functional component with Fc modification, presence or absence of sugar chain, disulfide bond formation of hinges, and presence or absence of drug binding.Home Antibody is not a medicine,"Platform material" to replace the surface and binding parts according to the applicationIt can be said that it is close to the existence (in this article).
And in the attachment of enhortsumaboidinIn combination with subcutaneous preparation (Belahi Arronidase Alpha compounding agent)is specifiedFactsNext chapterDosage formindicates that you are already assembled with combination therapy ( This article explains.
7. Subcutaneous Infusion – Put Alronidase in the same vial
From 2024 to 2025, the FDA has three checkpoint inhibitors.Subcutaneous InjectionApprovedFactsHome All"Fixed Dose Formulation" containing antibodies and hyalronidasesComment
The summary of the general theory that summarizes the challenges of high concentration protein preparation is: “Development of protein preparations that require high doses of mg/kg orders can be difficult in subcutaneous administration paths that require a protein concentration of 100 mg/mL or less than 1.5 mL of acceptable dose capacity.”Facts
and"The decomposition path that depends on the concentration is the biggest issue in developing protein preparations with high concentration."HOME "Reversible self-meeting may occur, which contributes to the nature of viscosity, etc., and makes it difficult to receive injections. High viscosity makes it difficult to produce high concentration protein by filtration.NotedFacts。
Nivolumab Subcutaneous Injection (OPDIVO QV、G) is attached to Hiallonidase (human recombinant)."Endoside glycosidedase, which is used to increase dispersion and absorption of drugs at the same time when subcutaneous administration"HOME "One-chain protein with a sugar chain, produced by CHO cells containing DNA plus content that codes soluble fragments of human hyalronidase (PH20)", and "61 weight is about 61 kDa"Facts。
action is temporary.Hyaluronan is a polysaccharide present in the extracellular matrix of subcutaneous tissue. It stabilizes the structure of the interstitial matrix, and the half-life of Hyaluronan is about 0.5 days. Toalonidase increases the permeability of subcutaneous tissue by temporarily degrading Hyaluronan.Home and"The effect of hyalronidase is reversible, the permeability of subcutaneous tissue is recovered within 24 to 48 hours."Facts。
KEYTRUDA QLEX is using another。.Bellahi Arronidase AlphaHomeHuman Hiallonidase PH20Home "Enhance dispersion and penetration, which enables the increase in the dosage capacity of Pembrolizumab, which is administered simultaneously under the skin"weightabout 49 kDa(Non-reduction/desaccharide chain conditions)Facts。
| 1 Vial contents (Attachment) | Additives | Dosage (indication of attachment) | |
|---|---|---|---|
| OPDIVO | Nivolumab 10 mg/mL | Mannitol, pentate, polyethylene 80, sodium, sodium. pH 6. | After di30 minutesContact Us |
| OPDIVO QVANTIG (Skin) | Nivolumab 600 mg+ Hiallonidase 10,000 units／5 mL(300 mg+5,000 units/2.5 mL) | Has cysteine, histidine hydrochloride, methionine, polyethylene 80, sucrose. pH 5.5~6.5. | abdo or thigh3 to 5 minutesSubcutaneous injection |
| KEYTRUDA | Pembrolizumab 25 mg/mL（100 mg／4 mL） | L-histidine, polyethylene 80, sucrose. 70 mg/mL. | After di30 minutesContact Us |
| KEYTRUDA QLEX (Skin) | Pembrolizumab 395 mg+ Bellahi Arronidase Alpha 4,800 units／2.4 mL(can be 790 mg+9,600 units/4.8 mL) | Has cysteine, histidine hydrochloride, methionine, polyethylene 80, sucrose. pH 5.3~5.9. | 2.4 mL1 minute4.8 mL2 minutesSubcutaneous injection |
| TECENTRIQ | Athesolizumab 1,200 mg／20 mL(also 840 mg/14 mL) | Acetic acid, L-histidine, polyethylene 20, sucrose. pH 5.8. | First time60 minutesIf there is any tolerance,30 minutesInfusion |
| TECENTRIQ HYBREZA (Skin) | Athesolizumab 1,875 mg+ Hiallonidase 30,000 units／15 mL | Has cysteine, methionine, polyethylene 20, sucrose. 1,232 mg. pH 5.8 in. | On the thighAbout 7 minutesSubcutaneous injection |
AllFacts(Reference Material 4-6) All three subcutaneous preparationsStore at 28°C and avoid vibration and shock.Facts。Dosage time is quoted to determine the preparation design, and it is not recommended to use drips and subcutaneous injections.
8. The calculation in this paper: how many times the concentration and how many mL is put in a minute?
Converts from table numbersThe calculation of this paper。
- Antibody Concentration:Nivolumab 600 ÷ 5 = 120 mg/mL(10 mg/mL for drip)12 times), Pembrolizumab 395 ÷ 2.4 = About 165 mg/mL(25 mg/mL)Approx. 6.6 times), atezolizumab 1,875 ÷ 15 = 125 mg/mL(1,200 ÷ 20 = 60 mg/mL)About 2.1 times）
- Shire et al.3 items"Over 100 mg/mL"Concentration is reached. On the other hand, dosage capacity is 2.4 to 15 mL,Approx. 1.6-10 times than 1.5 mLHome
- Injection Speed:Atezolizumab 15 mL ÷ about 7 minutes = Approx. 2.1 mL/minPembrolizmab 2.4 mL ÷ 1 min = 4.8 mL ÷ 2 min = 2.4 mL/minNivolumab 5 mL ÷ 3 to 5 minutes = 1.0 to 1.7 mL/min
- Enzyme Concentration:Nivolumab 10,000 units ÷ 5 mL, Pembrolizumab 4,800 units ÷ 2.4 mL, Atezorizumab 30,000 units ÷ 15 mL —3 units of just 2,000 units/mLHome
- Concentration of sugar (suc ):Pembrolizumab subcutaneous 168 mg ÷ 2.4 mL = 70 mg/mL(same as for dripping), atherosmab subcutaneous injection 1,232 ÷ 15 = About 82 mg/mL
Premises and Limits:The concentration is the value divided by the volume of the vial. Shire et al. reported that a general estimate of 1.5 mL or less is indicated by the general theory as of 2004, not as design criteria for individual products.Matching on calculationThis document is not included. These numbers are used to see the assembly of preparations.It does not indicate the effect, safety, or superiority of the method of administration.
9. Perspective of material ians 2: “High Concentration Protein” and “Enzyme” together
If you read the description of the attachment in the words of the material, the mechanism of subcutaneous preparation isGel Mesh T Disassembly(This article explains).
- Bengali"Polysaccharides present in extracellular matrix of subcutaneous tissue"HomeHalf-life is about 0.5 daysand the structure component is fast to replaceFacts
- arronidase it"Turn off"to increase transparency and effectRecover within 24 to 48 hoursFacts
In other wordsLocally reduce the molecular weight of the polymer mesh, making it easier for the drug to flow.It is. In addition to changing the liquid (high concentration and high viscosity) of the infusion side,Lowering media resistance on the side receivingDutch It is a problem that pushes the fluid into a porous body,Both fluid and medium sideIt is the idea that This article explains. Since the mesh is originally a fast-changing material,"Return to the original even if it breaks temporarily"Contact Us
For subcutaneous preparation containers,Approx. 145-149 kDa antibodyHomeThe molecular weight is approximately 49-61 kDa.Contact UsFactsHome Antibody120〜165 mg/mLHigh concentrationThe calculation of this paperEnzymeUnit ( e)Displayed inFacts。
As noted by Shire,The biggest challengeandReversible self-meeting increases viscosity and makes it difficult to manufacture by filtrationFactsHome In the liquid,Another protein (enzyme) must keep activeHome What is required?Contains "Dark and not cohesive" and "Don't damage each other" at the same time(This article explains).
Compared to the list of additives, one trend is determined.Facts。
- All three subcutaneous preparationsHomeContains quinine, methionine, polyethylene glycol, and glucose.Contact Us
- For dripOPDIVO・KEYTRUDA・TECENTRIQThe additives listed in the attachment are:No methionine
Since the attachment does not describe the purpose of each additive, this article does not determine the reason for adding methionine. CloseWhen the formulation is high concentration and it is same as the , there is a common ingredientthe fact that It is worth reading as a clue of compound design (in this article).
Chapter 8Three products are matched with 2,000 units/mL.HomeThe calculation of this paperHome Three products and antibodies (two products are PH20 soluble fragments, one product is modified).Enzyme amount per capacitance is increasedHome Sorry, this entry is only available in Japanese.The combination on the antibody side is the 'common prescription value' that does not depend on the antibody.Please note that this article explains the possibility.
10. Approval status (reco zed by regulatory authorities)
| Product | Type | First Approval (FDA) | Remarks |
|---|---|---|---|
| YERVOY | Infusion | March 25, 2011（BLA 125377） | Antibody for CTLA-4 |
| KEYTRUDA | Infusion | September 4, 2014（BLA 125514） | Some efficacy in the attachmentQuick approvalNotice |
| OPDIVO | Infusion | December 22, 2014（BLA 125554） | According to the application material published by PMDA (created by Ono Pharmaceutical Industry)July 2014approved as "Opgybo drip static injection 20 mg, same as 100 mg" in the US December 2014Quick approval |
| TECENTRIQ | Infusion | May 18, 2016（BLA 761034） | IgG1 |
| TECENTRIQ HYBREZA | Subcutaneous injection (contained with hyalronidase) | September 12, 2024(BLA 761347, Standard Review) | Athesolizmab + Hiallonidase - tqjs |
| OPDIVO QVANTIG | Subcutaneous injection (contained with hyalronidase) | December 27, 2024(BLA 761381) | Nivolumab + Hiallonidase -vvhy |
| KEYTRUDA QLEX | Subcutaneous injection (contained with Bellahi Arronidase alpha) | September 19, 2025(BLA 761467, priority screening) | Pembrolizumab + Bellahi Arronidase Alpha-pmph |
FDA Drugs@FDA [Reference Material 12] for Approval Dates and Examinations, FDA Drugs and Quick Approvals are subject to each attachment [Reference Material 4-10] and PMDA Public Reference Material 15 for domestic approvalFactsHome Drugs@FDA has two OPDIVO QV Gs: BLA 761381 and 761429.The approval status of three subcutaneous injection products in Japan (PMDA) is not confirmed at the time of the investigation of this article (September 2026)Undetermined / Future。
- Checkpoint in tors block binding to T-cell brakes (CTLA-4, PD-1) and their opponents (PD-L1) with antibodyFacts
- The type of antibody is different from the product.IgG1, IgG4, and Fc modified and non-saccharide-added IgG1 are replaced by Pro.Facts
- IgG4 half-formation and Fab-arm replacement is a chemical phenomenon involving dihydride linkage.Facts
- Many efficacy is written in a set called “FDA-approved inspection”.There are three plugs of PD-L1, MSI-H/dMMR, TMB-HFacts
- In subcutaneous injection, the antibody concentration is about 2.1-12 times that of intravenous drips, and the concentration is 2,000 units/mL for the three products.The calculation of this paper
- Alronidase temporarily depolyses the subcutaneous tissue Hialronan, and the permeability returns in 24 to 48 hoursFacts
11. Glossary
- Immune checkpoint
- Brake mechanism to prevent excessive activation of the immune system. CTLA-4, PD-1, etc.
- CTLA-4
- Negative modulation factor of T-cell activity. The source is with CD80/CD86.
- PD-1
- receptors on T cells. When PD-L1 and PD-L2 are combined, growth is suppressed.
- PD-L1
- PD-1 Can be expressed in the immune cells invaded in tumor cells and tumors.
- IgG1／IgG4
- Subclass of antibody. The properties of hinge and Fc differ.
- Home
- The part that connects the Fab arm and the Fc of the antibody. There is a disulfide bond between the chains.
- Fab-arm replacement
- The halves of IgG4 are replaced with another IgG4 halves.
- Fc modification
- Change the amino acids and sugar chains of Fc and adjust the work of calling immune cells.
- Antibody Dependent Cell Injuries (ADCC)
- The function that the immune cell injures the target cell through the Fc of the antibody.
- CPS／TPS
- PD-L1 indicator to indicate the positivity of dyeing. Used for threshold of judgment.
- MSI-H／dMMR
- Microsatellite instability / Mismatch repair defects.
- TMB-H
- High tumor gene mutations. variant/mega base.
- Alronan
- Polysaccharides in extracellular matrix of subcutaneous tissue.
- Alronidase
- Enzyme decom。 arronan. Increase dispersion and absorption by subcutaneous preparation.
- PH20
- A type of human hyalronidase. The soluble fragments and variants are used for the preparation.
- Fixed dose formula
- One formulation of multiple active ingredients.
- Self-Meeting
- Collecting protein reversibly. The viscosity increases.
- Quick approval
- FDA System. Approve in an alternative evaluation item and ask for verification in the verification test.
12. Reference materials (primary information)
- The Nobel Assembly at Karolinska Institutet"The Nobel Prize in Physiology or Medicine 2018 — Press release" October 1, 2018 — nobelprize.org
- Ishida, Y., Agata, Y., Shibahara, K., Honjo, T.「Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death」The EMBO Journal 11(11), 3887–3895 (1992). doi:10.1002/j.1460-2075.1992.tb05481.x — pmc.ncbi.nlm.nih.gov
- Leach, D.R., Krummel, M.F., Allison, J.P.「Enhancement of antitumor immunity by CTLA-4 blockade」Science 271(5256), 1734–1736 (1996). doi:10.1126/science.271.5256.1734 — pubmed.ncbi.nlm.nih.gov
- DailyMed「OPDIVO (nivolumab) injection」 — dailymed.nlm.nih.gov
- DailyMed「OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection」 — dailymed.nlm.nih.gov
- DailyMed「KEYTRUDA (pembrolizumab) injection」 — dailymed.nlm.nih.gov
- DailyMed「KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) injection」 — dailymed.nlm.nih.gov
- DailyMed「TECENTRIQ (atezolizumab) injection」 — dailymed.nlm.nih.gov
- DailyMed「TECENTRIQ HYBREZA (atezolizumab and hyaluronidase-tqjs) injection」 — dailymed.nlm.nih.gov
- DailyMed「YERVOY (ipilimumab) injection」 — dailymed.nlm.nih.gov
- DailyMed「PADCEV (enfortumab vedotin-ejfv)」 — dailymed.nlm.nih.gov
- FDADrugs@FDA: FDA-Approved Drugs — accessdata.fda.gov
- Vidarsson, G., Dekkers, G., Rispens, T.「IgG subclasses and allotypes: from structure to effector functions」Frontiers in Immunology 5, 520 (2014). doi:10.3389/fimmu.2014.00520 — pmc.ncbi.nlm.nih.gov
- Shire, S.J., Shahrokh, Z., Liu, J.「Challenges in the development of high protein concentration formulations」Journal of Pharmaceutical Sciences 93(6), 1390–1402 (2004). doi:10.1002/jps.20079 — pubmed.ncbi.nlm.nih.gov
- PMDA Publication Materials (Created by Ono Pharmaceutical Co., Ltd.)"Document about 20 mg of OPSYBO drip static injection, 100 mg of OPSYBO drip static injection" 2016 (PDF) — pmda.go.jp
13. Response Table of Claim and Source (Audit)
| Content | Home | |
|---|---|---|
| The Nobel Prize in Physiology and Medicine in 2018 was awarded to Allison and Honda to discover cancer treatment by in。ting the control of the negative immunity. A strategy that in ts the immune system brake has shown that it can be used for cancer treatment. Axel and brake balance are essential to avoid autoimmune destruction. Allison studied CTLA-4 at University of California Berkeley in the 1990s and observed acting as a brake of T cells. The first experiment was the end of 1994. In 1992, Honda discovered PD-1 and studied at Kyoto University showed that PD-1 works in different ways as a brake as well as CTLA-4. Side effects can be severe and life-threatening caused by autoimmune reactions due to excessive immune response | Nobel Prize 2018[Reference 1]https://www.nobelprize.org/prizes/medicine/2018/press-release/ | Facts |
| Isolated the PD-1 gene, a new member of the immune globulin gene super family by subtractive hybridization from the cell strain that causes program cell death | Ishida et al[Reference 2]https://pmc.ncbi.nlm.nih.gov/articles/PMC556898/ | Facts |
| Con that in vivo administration of antibodies to CTLA-4 causes tumor rejection including already established tumors, blocking the in tory effect of CTLA-4 can affect and strengthen effective immune responses to tumor cells (experiment in mice) | Leach et al (1996)[Reference 3]https://pubmed.ncbi.nlm.nih.gov/8596936/ | Facts |
| Nivolumab is expressed by IgG4 current immunoglobulin (human IgG4), with a weight of 146 kDa, recombinant CHO cell. OPDIVO is 10 mg/mL, and it is OPpH 6 of mannitol, pentate, polyethylene 80, sodium, and sodium acetate. The binding of PD-L1 and PD-L2 to PD-1 suppresses the growth of T cells and cytokine production and increases PD-1 ligand in some tumors. Inhibition of the combination of Nivolumab and Ipilimumab increased antitumor activity due to double blocking of PD-1 and CTLA-4 in mice-like tumor models. | OPDIVO[Reference 4]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394 | Facts |
| OPDIVO QV G is a fixed dose formula for nivolumab and hyaluronidase (human recombinant). The hyaluronidase increases the dispersion and absorption of concurrent medications at the time of subcutaneous administration. It is a single-chain protein with sugar chains produced by CHO cells, including plus CHO that codes soluble fragments of human PH20, and approximately 61 kDa. 600 mg+10,000 units/5 mL and 300 mg+5,000 units/2.5 mL, additives (histidine, histidine hydrochloride, methionine, pentate, polyethylene 80, sucrose), pH 5.5–6.5. Injecting subcutaneously for 3-5 minutes on the abdomen or thighs, save at 2-4 °C and avoid shaking and vibration. Alarum is a polysaccharide in the extracellular matrix of subcutaneous tissue, with a half-life of about 0.5 days. The hyaluronidase temporarily depolymerizes and increases transparency, and the effect is reversible and recovers within 24 to 48 hours. | OPDIVO QV G[Reference 5]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f8c38fa-42f4-4387-9e8c-7a1c66855d8b | Facts |
| Pembrolizumab is produced by humanized monoclonal IgG4 current antibody, with a weight of about 149 kDa, and recombinant CHO cells. KEYTRUDA contains 100 mg/4 mL (25 mg/mL) with L-histidine polyethylene 80 and sucrose 70 mg/mL, and dripping over 30 minutes after infusion. Some efficacy must be approved quickly. PD-L1 (CPS ≥1), MSI-H/dMMR solid carcinoma, TMB-H (≥10 mutations/megabase) solid carcinomas are evaluated by the FDA, and PD-L1 IHC 22C3 pharmDx was used in clinical trials. PD-L1 (CPS ≥10) triple negative breast cancer primary treatment with local or metastatic urinary tract cancer combined with enfortumab vedotin. | KEYTRUDA[Reference Material 6]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287 | Facts |
| KEYTRUDA QLEX is a fixed-dose formulation of PEMBROLIZUMAB and BELAHERALRONIDAS alpha, the BELAHERALRONIDAS alpha is a modified end-glycosidedase of human hyaluronidase PH20 that increases dispersion and penetration, and the 49 weight is about 49 kDa (non-reaccharide condition). 395 mg+4,800 units/2.4 mL and 790 mg+9,600 units/4.8 mL, additives (histidine, histidine hydrochloride, methionine, polyethylene 80, sucrose 168 mg/2.4 mL), pH 5.3-5.9. Inject 2.4 mL for 1 minute and 4.8 mL for 2 minutes. Save at 28°C, avoid vibration and shock, and restore transmittance within 24 to 48 hours. | KEYTRUDA QLEX[Reference Material 7]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=097d166f-b73b-41d3-9b37-7653cd2a0c41 | Facts |
| Atherosidmab is a PD-L1 antibodies that are Fc modified, humanized, and non-saccharide-added IgG1 current immunoglobulin, and 145 weight 145 kDa. TECENTRIQ is 1,200 mg/20 mL and 840 mg/14 mL, with acetic acid, L-histidine, polyethylene 20 and sucrose, and should be poured in 30 minutes after the initial 60 minutes and tolerance. PD-L1 PDs antitumor immunity responses without in antibody-dependent cell injuries by binding to PD-L1 and blocking interactions with PD-1 and B7.1. | TECENTRIQ[Reference 8]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee | Facts |
| TECENTRIQ HYBREZA is a fixed-dose compound of Atezolizumab and hyaluronidase (human recombinant, PH20 soluble fragments, about 61 kDa), 1,875 mg+30,000 units/15 mL, additives (histidine 46.5 mg, methionine 22.4 mg, polyethylene 20 9 mg, sucrose 1,232 mg), pH 5.8 in acid, subcutaneous injection over thighs, oscillation in between 2 to 8°C and 24 hours. | TECENTRIQ HYBREZA[Reference 9]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a617b089-ce66-464b-987b-b45d029b4d6f | Facts |
| Iguamumab is produced by CTLA-4 antibody recombinant IgG1-current immunoglobulin, 148 weight of 148 kDa, and CHO cell culture. CTLA-4 is a negative modulation factor for T-cell activity, and icymumab binds to CTLA-4 to block interaction with CD80/CD86 | YERVOY[Reference Materials 10]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2265ef30-253e-11df-8a39-0800200c9a66 | Facts |
| Enhertsmab chidotin is effective in preoperative and postoperative treatment of myocardial invasive boder cancer in combination with embrozsmab, or with embrozsmab and Bellahyaluronidase alpha. | PADCEV[Reference Materials 11]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5631d3e-4604-4363-8f20-11dfc5a4a8ed | Facts |
| FDA approval date and examination classification (YERVOY 25 March 2011 / BLA 125377, KEYTRUDA 4 September 2014 / BLA 125514, OPDIVO 22 December 2014 / BLA 125554, TECENTRIQ 18 May 2016 / BLA 761034, TECENTRIQ HYBREZA 12 September 2024 / BLA 761347 · Standard examination, OPDIVO QV27G 27 December 2024 / BLA 761381 and BLA 125554, TECENTRIQ 2016 / BLA 761034, TECENTRIQ HYBREZA | FDA Drugs[Reference Material 12]https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | Facts |
| The core hinge of IgG4 is CPSC, and it is easy to form a chain di。fide between 226 and 229 cysteins than CPPC of IgG1, and half-child (one H-chain and one L-chain) that is not connected with a shared bond is observed. S228P variant with IgG1 type core hinge does not form half child. Half of IgG4 is randomly reconnected with other IgG4 halves (Fab-arm replacement) and controlled by oxidative reduction conditions | Vidarsson et al )[Reference 13]https://pmc.ncbi.nlm.nih.gov/articles/PMC4202688/ | Facts |
| The development of high-dose protein drugs is difficult in subcutaneous administration paths that require a concentration of more than 100 mg/mL in less than 1.5 mL, and the reversible self-session contributes to viscosity and makes it difficult to do by injection. | Shire et al (2004)[Reference 14]https://pubmed.ncbi.nlm.nih.gov/15124199/ | Facts |
| Nibolumab is a genetically modified human IgG4 mono。nal antibody that replaces the H-chain 221th amino acid residue with Pro. It is produced by CHO cells with 2 440 residue H-chains and 2 L-chainseries. In July 2014, “Opgybo drip static injection 20 mg, 100 mg” in Japan has been approved for efficacy and effect of malignant melanoma, and has been approved in December 2014 in the U.S. (by materials created by Ono Pharmaceutical Co., Ltd. and published by PMDA) | PMDA Publication Materials (Opgybo drip static injection, Ono Chemical Industry)[Reference Materials 15]https://www.pmda.go.jp/drugs/2016/P20161208002/180188000_22600AMX00768_B100_1.pdf | Facts |
| 120 mg/mL (12 times), 165 mg/mL (approx. 6.6 times), 125 mg/mL (approx. 2.1 times) Dosage capacity 2.4 to 15 mL is about 1.6 to 10 times. The injection speed was about 2.1 mL/min, 2.4 mL/min, 1.0 to 1.7 mL/min. The concentration of s is 2,000 units/mL. 70 mg/mL, about 82 mg/mL 1,308 residues from H-chain and L-chain residues | 。ulation of this article. The concentration is the value divided by the volume of the vial, and the roughness of Shire is not the design standard of individual products in general description. It does not indicate the effect, safety, or superiority of the method of administration | The calculation of this paper |
| Approval status in Japan (PMDA) of three subcutaneous preparations | Not confirmed at the time of investigation (September 2026) | Undetermined / Future |
| Methionine and other additives are formulated, because the concentration of three enzymes matches, whether the "221th" and "S228" are the same position, the design without sugar chain affects manufacturing management, the composition of the test reagent. | I can not confirm the primary information referenced in this article. | |
| Inferiority and effect of each product, clinical performance, safety evaluation, drip and subcutaneous injection | This article is an explanation of antibody design and formulation technology, and does not evaluate the effects and safety of treatment. The dosage time and concentration are quoted in the attachment to determine the preparation design. | |
| IgG4's hinge substitution is arranged according to the design that stops the skeletal stiffness of the exchange of dynamic shared bonds. Preparation of non-saccharide chain addition to surface treatment as a "discharging" design. Platformation of antibody into "transportation material", "shielding material", and "platform material". The subcutaneous tissue shall be temporarily loosened by hydrogel and hyaluronidase. I read high concentration antibodies and residence as a compound design issue. Read additives common to subcutaneous preparation. Inspection threshold and repeatability. | Also commentary of this article based on the publication content. It is not the opinion of authors, regulators and companies of each paper. | |
| Fig. 1 - Fig. 4 is a diagram for explanation, not the actual structure, cell, and device. Hero image and figure 5 are AI-generated images. | Notes by this article |
Last Updated: September 26, 2026 / Source is limited to primary information (Nobel Foundation announcements, FDA approval attachments, and Drugs@FDA, PMDA publications, and reader review papers). They are distinguished from the facts that have been sourced as "explanation" because they include antibody design and formulation design. We do not describe the purpose of compounding additives, the reason why the concentration of s and the status of approval in Japan of subcutaneous preparations, because it was not confirmed by the public primary information. The general structure and manufacturing of antibodies are handled in this series "Antibody Medicine and ADC". This article explains antibody design and formulation technology.It does not evaluate the effectiveness and safety of the treatment, but it is not medical advice. All diagrams are illustrations for explanation. Fig. 1 - Fig. 4 is a vector drawing, and figure 5 is an AI-generated image.We do not show actual s, cells, and products.