{"id":5327,"date":"2025-09-18T16:43:43","date_gmt":"2025-09-18T22:43:43","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=5327"},"modified":"2025-09-26T10:57:45","modified_gmt":"2025-09-26T16:57:45","slug":"prof-brambells-fcrn-the-story-so-far","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2025\/09\/18\/5327\/prof-brambells-fcrn-the-story-so-far\/","title":{"rendered":"Prof Brambell’s FcRn \u2013 The Story So Far"},"content":{"rendered":"\n
\"\"<\/a><\/figure>\n\n\n\n

Francis William Rogers Brambell was an Irish scientist who rose to prominence in the middle of the last century.\u00a0 He is remembered for 2 major accomplishments.\u00a0 First and foremost, his discovery that passive immunity is transferred from mother to baby.\u00a0 Based on research in various animal species on the transfer of protective immunity,\u00a0he postulated a receptor and transport system for gamma-globulins during intrauterine and early postnatal life for humans, as well. \u00a0As envisioned by him, this shuttle mechanism is based on a specific receptor, that uniquely recognizes g-globulins and ferries them from the gut to the bloodstream without loss of biological activity.<\/p>\n\n\n\n

Several decades later, his assumptions were proven to be correct when the presence of a rather unique receptor was confirmed.  We are of course referring to the discovery of the FcRn (Fc receptor neonatal), also appropriately named and referred to as the Brambell receptor.<\/p>\n\n\n

\n
\"\"<\/a>
Prof. F.W.R.Brambell<\/figcaption><\/figure>\n<\/div>\n\n\n

His second significant contribution is to animal welfare.  He was a zoologist and an early animal rights activist who cared about animal husbandry and the conditions in which animals are kept.  He advocated the \u2018Five Freedoms\u2019 which have been adopted worldwide.  We won\u2019t discuss this program here in greater detail as the topic of this blog is the FcRn, its amazing history and therapeutic importance in medicine.<\/p>\n\n\n\n

When Brambell gave a lecture series in 1957 summarizing his studies [1]<\/a>, our understanding of antibodies was still fairly rudimentary.\u00a0 He knew of course that antibodies were found in the gamma-globulin fraction on serum electrophoresis, providing protection from antigenic challenges in the form of immunity.\u00a0 However, knowledge of structural details of immune globulins was still in its infancy.\u00a0 All that was known was their size at the time, but this was about to change.[2]<\/a><\/p>\n\n\n\n

Only some 10 years later, Edelman and his team at the Rockefeller Institute were able to determine the aminoacid composition of IgG, the largest protein to be analyzed at the time (150 kDa).[3]<\/a>,[4]<\/a><\/p>\n\n\n\n

Edelman\u2019s sequencing work was only possible by breaking down the overall size of the IgG molecule.  He did this by proteolytic degradation and separation of disulphide S-S connections between heavy and light chains. They also made use of the paraprotein found in vast quantities in the blood of multiple myeloma patients, and the protein in the urine of these patients known as Bence Jones protein.  As they discovered, the latter was the L-chain (usually kappa) of the monoclonal IgG produced by the cancerous B-cells.<\/p>\n\n\n

A fundamental understanding of immunological problems requires chemical analysis\u00a0 EDELMAN <\/span><\/span>[5]<\/a><\/p>\n<\/div>\n\n\n\n

A short excursion into history is in order here.\u00a0 In 1847, Bence Jones [6]<\/a>\u00a0examined the urine of an multiple myeloma patient.\u00a0 The isolated urinary protein behaved in a way not typical for known proteins: on heating it coagulated only to dissolve again at higher temperatures.[7]<\/a>\u00a0 The histopathologic report was provided by no other than the well-known ophthalmologist and Renaissance man John Dalrymple.[8]<\/a>\u00a0 His autopsy findings are described in a separate article.\u00a0He detected \u2018mollities ossium\u2019 or osteomalacia in the vertebrae and ribs of this patient with segmental lesions rich in mononuclear cells that he recognized as being \u2018morbid\u2019.<\/p>\n\n\n\n

When the FcRn was eventually discovered in the 90\u2019s, its function became clearer.\u00a0 By preventing lysosomal degradation and recycling intact proteins back into circulation, this receptor prolongs the half-life of serum albumin and IgGs immensely.\u00a0Without rescue by the FcRn, albumin would be broken down requiring much higher liver synthetic function in order to compensate, and IgGs would only have a 3-5 day half life (instead of 3 weeks).[9]<\/a><\/p>\n\n\n\n

The last 20 years have seen the advent and clinical development of several FcRn inhibitors.\u00a0The intent is to reduce the recycling of disease-causing autoantibodies that drive the pathology of many autoimmune diseases.[10]<\/a><\/p>\n\n\n\n

None of these FcRn inhibitors discriminate between \u2018good\u2019 protective and \u2018bad\u2019 autoreactive IgG; they block the recycling of any and all IgG molecules to the same degree.<\/p>\n\n\n\n

The question then becomes: Is there a net benefit?  How much is gained by reducing autoantibodies while also losing protective IgG and albumin?  What about the risk of infections? Fortunately, all this is testable in clinical trials, and the verdict is in: for most autoimmune conditions (gMG, CIDP, ITP) there is a clear clinical benefit to this.<\/p>\n\n\n

\n
\"\"<\/a>
From Pyzik \/ Ref. 10<\/figcaption><\/figure>\n<\/div>\n\n\n

<\/p>\n\n\n\n

As it turns out, hypogammaglobulinemia rarely gives rise to significant illness and is surprisingly well tolerated.  Even patients with Bruton\u2019s X-linked agammaglobulinemia can cope with the total loss of protective IgG.  Of course, approved FcRn blockers are not capable of achieving a state of absolute agammaglobulinemia; these drugs only achieve 60-70% inhibition, never resulting in complete 100% blocking action. In addition, there is a dose-related response in IgG serum levels that can be monitored easily.<\/p>\n\n\n\n

In contrast to other Fc receptors, the FcRn is not involved in downstream intracellular signaling.\u00a0 At least this was the opinion until a few years ago, but newer studies challenge this assumption.\u00a0Come to think of it, the FcRn \u03b1-chain does have an intracellular component that could be involved in intracellular signaling (see image above).\u00a0This is being studied as we speak.<\/p>\n\n\n\n

Ideally, we would like to have drugs with little effect on albumin-recycling, predominantly affecting IgG- recycling.  We would also like to have drugs with little inhibition of recycling of protective IgGs.  Research on the FcRn binding pocket suggests that albumin attaches to FcRn at a different location from where IgGs are bound; thus, small-sized inhibitors that do not create allosteric interference with albumin-binding would be expected to have higher selectivity.  This was borne out for efgartigimod\/Vyvgard, a rather small molecule (54 kD).  In contrast, full-sized mAb are less or non-selective and affect albumin recycling to various degrees.<\/p>\n\n\n\n

None of the approved FcRn inhibitors selectively target only pathologic antibodies in the mixture of IgGs.  Neutralizing or eliminating a particular autoantibody specifically, say, the AChR antibody in gMG, would seem advantageous, at least conceptually.  Seldegs are constructs with autoantibody specificity and showed promise in MOGAD and possibly other neurologic diseases.[11]<\/a>,[12]<\/a>  At this time it remains unclear whether Seldegs can be titrated to higher efficacies than existing non-selective FcRn inhibitors.<\/p>\n\n\n\n

There are other interesting aspects of the FcRn, related to its function as a transport molecule of macromolecules, which are worth exploring in the years ahead.  We will talk more about this in an upcoming posting.  Brambell already realized that work on FcRn touches and cross-connects to some of the biggest problems in biology that are still unsolved. We quote:<\/p>\n\n\n

\u2026interest in the transmission of passive immunity centres on the problem of how such large molecules are transported from the circulation of the mother to that of the young across the intervening cellular barriers.\u00a0 BRAMBELL<\/span><\/span><\/p>\n<\/div>\n\n\n\n

This Irishman was way ahead of his times.  His research commands respect, and his analytical approach is impressive.  His ability to logically analyze experimental data and  come up with solutions to biologic puzzles was nothing short of extraordinary.<\/p>\n\n\n\n

Chapeau to Prof. Brambell, a man who deserves our admiration.<\/p>\n\n\n\n

\n\n\n\n

ABBREVIATIONS
<\/strong>Seldeg                    selective depletion of antigen-specific antibodies
MOGAD                  Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease
gMG                        generalized myasthenia gravis
ITP                           immune thrombocytopenic purpura
CIDP                        Chronic Inflammatory Demyelinating Polyneuropathy
FcRn                        Fc receptor neonatal = Brambell receptor<\/p>\n\n\n\n

REFERENCES
<\/strong>[1]<\/a> Brambell F.  The passive immunity of the young mammal.  Biological Reviews, 1958, 33: 488
[2]<\/a> He quotes MW of 160 and 850 kDa based on ultrafiltration data, fairly accurate estimates for IgG and IgM, respectively
[3]<\/a> Edelman G.  The Structure and Function of Antibodies. Scientific American, 223: 34, 1970
[4]<\/a> By contrast, insulin, the largest protein sequenced till then (by Sanger) had a MW of 5,808 Da and was composed of 510 AA and thus considerably smaller
[5]<\/a> Edelman G. Antibody Structure and Molecular Immunology. Nobel Lecture 1972  https:\/\/www.nobelprize.org\/prizes\/medicine\/1972\/edelman\/lecture\/<\/a>  Accessed Sept. 17, 2025
[6]<\/a> His full name is actually Henry Bence Jones
[7]<\/a> Jones H. On a new substance occurring in the urine of a patient with mollities ossium. Philosophical Transactions of the Royal Society. 138: 55, 1848
[8]<\/a> Dalrymple J. On the Microscopical Character of Mollities Ossium. Dub Quart J Med Sci 2, 85, 1846
[9]<\/a> Bussel J.  Neonatal Fc Receptor – Biology and Therapeutics.  NEJM 392: 1621, 2025
[10]<\/a> Pyzik M.  The therapeutic age of the neonatal Fc receptor.  Nature Reviews Immunol 23: 415, 2023
[11]<\/a> Devanaboyina S.  Engineered clearing agents for the selective depletion of antigen-specific antibodies.  Nature Communications, 8, Article number: 15314, 2017
[12]<\/a> Sun W.  Selective Depletion of Antigen-Specific Antibodies for the Treatment of Demyelinating Disease.  Mol Ther 29: 1312, 2021<\/p>\n\n\n\n

<\/p>\n\n\n\n\n\n

<\/p>\n","protected":false},"excerpt":{"rendered":"

Francis William Rogers Brambell was an Irish scientist who rose to prominence in the middle of the last century.\u00a0 He is remembered for 2 major accomplishments.\u00a0 First and foremost, his discovery that passive immunity is transferred from mother to baby.\u00a0 Based on research in various animal species on the transfer Continue reading Prof Brambell’s FcRn \u2013 The Story So Far<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":5339,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[140,227,18],"tags":[2424,381,2410,1271,2420,2295,2419,2403,2412,2417,2404,2413,2296,2408,2214,1583,2411,2409,2405,2425,2415,2421,1021,2213,2422,2418,2407,2423,2416,2406,2414],"class_list":["post-5327","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-interesting_facts","category-recent_literature","category-the_viewpoint","tag-achr","tag-agammaglobulinemia","tag-albumin-recycling","tag-allphase-pharma-consulting","tag-b-cells","tag-batoclimab","tag-bence-jones-protein","tag-brambell-receptor","tag-brutons-x-linked-agammaglobulinemia","tag-dalrymple","tag-edelman","tag-efgartigimod","tag-fcrn","tag-fcrn-inhibitors","tag-gmg","tag-harald-reinhart","tag-hypogammaglobulinemia","tag-igg-recycling","tag-igg-sequencing","tag-insulin","tag-insulin-sequencing","tag-intracellular-signaling","tag-multiple-myeloma","tag-myasthenia-gravis","tag-nipolimab","tag-osteomalacia","tag-passive-immunity","tag-roxanolizumab","tag-sanger","tag-seldeg","tag-vyvgard"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2025\/09\/HR_SLIDER-BRAMBELL.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-1nV","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":4599,"url":"https:\/\/allphasepharma.com\/dir\/2025\/06\/29\/4599\/pk-pd-of-biologicals\/","url_meta":{"origin":5327,"position":0},"title":"PK\/PD 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