NephMadness 2014 Part 8 - Biologics Bracket

This is a really exciting bracket and is full of new agents that will hopefully lead to major advances in our field. Acthar is the outlier here as, even though it is a peptide, it is not an antibody. For all the other agents I find it helpful to visualize what the antibody is targeting and on which cell type. Hopefully these cartoons will help. I think Rituximab and bortezomib should always go hand in hand when treating and auto- or alloimmune process as rituximab eliminates immature and naïve B cells and bortezomib eliminates B cells that have matured into antibody producing Plasma cells. There are some small trials reporting the use of both agents including a phase 2 trial in Waldenstroms Macroglobulinaemia but a large clinical trials using both these agents would be great.

In 2005 the FDA approved abatacept for RA after clinical trials showed benefit. However, there was evidence that this biologic might not be so efficacious in transplantation. Co-stimulation blockade on individual CD4+ T helper-cell subsets suggested a resistance of IL-17 secreting CCR6+ memory type 17 T helper cells (TH17) cells to CD28 and CTLA-4 blockade by abatacept. Effectively, abatacept inhibits the responsiveness of the total population, but a subset of cells are resistant to this inhibition. Belatacept is a second-generation CTLA-4 Ig fusion protein that differs from abatacept by only 2 amino acid substitutions (L104E and A29Y), which gives rise to slower dissociation rates from both CD86 and CD80. Subsequent research revealed this agent to be 10-fold more potent in vitro, and a more effective inhibitor of renal transplant rejection than abatacept. The subsequent BENEFIT trials proved belatacepts efficacy in transplantation.

CR1 or complement receptor type 1 or C3b/C4b receptor or CD35 is protein encoded the CR1 gene. This gene is in the RCA (regulators of complement activation) cluster region of human chromosome 1. This region includes the CFHR 1-5 and CFH genes. All these genes when mutated can cause immune-complex glomerular diseases such as MPGN. This CR1 protein also accounts for all the Knops blood group antigens. Reductions in CR1 or down regulating mutations can also cause SLE. Soluble CR1 may be useful in transplantation also. One study showed that sCR1 treatment improved 24 hour creatinine and inflammatory profiles post transplant in rats transplanted after brain death.

As precursors to the plasma cells that secrete antibodies, B cells are central in the pathology of SLE. Increased B-cell activation is due in part to increased levels of growth factors, including B-lymphocyte stimulator (BLyS), also called B-cell activating factor (BAFF). Belimumab is a human IgG1 monoclonal antibody that binds to soluble BLyS and thus prevents it from binding the BAFF receptors on B cells. So you can see where the trial names BLISS-52 and BLISS-76 come from, the numbers refer to the number of weeks the trials lasted. BLyS is a growth factor required for B-cell survival, maturation, and activation; germinal-center formation; the development of B cells into plasma cells; and immunoglobulin production. Many maturing B cells are completely dependent on the binding of BAFF receptors by BLyS to survive and mature. Memory B cells cells lack BAFF receptors. At least 50% of people with SLE have elevated plasma levels of soluble BLyS and there is a weak but significant correlation between high levels and active disease. Unfortunately patients with severe active LN were excluded from the BLISS trials.

For me Rituximab was the favourit in this groups as it is probably used in the greatest variety of diseases.

Thanks for reading and i hope you all learned something as i learned alot from NephMadness 2014. Now go to the NephMadness site and submit your brackets if you have not done so already!

Antibody-Mediated Rejection: Choose your weapons

Acute humoral or antibody-mediated rejection (AMR) is attributed to the presence of alloantibodies against the graft, which could be either antibodies against human leukocyte antigens (HLAs) Class I and/or II , non-HLA antigens or endothelial antigens. Diagnosis of AMR is made through tissue biopsy and presence of alloantibodies. Early treatment is of paramount for the preservation of graft function. Treatment strategies include removal of alloantibodies, decreasing or stopping production of alloantibodies, or attenuating the immune systems response to alloantibodies. 

Plasmapheresis/Plasma Exchange 

Removal of alloantibodies is done through the use of plasmapheresis/plasma exchange or immunoadsorption. Plasmapheresis, or removal and replacement of one plasma volume, is effective at removing approximately 60% of the intravascular IgG which accounts for about 75% of the intravascular immune response. Extravascular IgG equilibrates in about 48 hours thus reducing total body IgG concentrations and reducing the effective immune response. Immunoadsorption works similarly to plasmapheresis except that plasma immune complexes and IgG are removed via protein A bound silica matrices. In the latter, the remaining plasma components are returned to the patient without the need for plasma exchange. FFP is needed even on the first run of plasmapheresis if recent biopsy was performed (prevention of bleeding). The cost of 5 treatments is about $4,600. 

Intravenous Immune Globulin 

Infusion of intravenous immunoglobulins (IVIG) has been studied at doses of 10 grams to 2 gm/kg as monotherapy or in conjunction with plasmapheresis or B-cell depleting agents. The mechanism of action is not entirely known but it is thought that neutralization of alloantibodies occurs when bound by the anti-idiotypic antibodies in IVIG as well as diminished plasma cell production by increasing total body concentrations of immunoglobulins and direct T-cell and complement cascade effects. Cost for IVIG is $77.06/gm resulting in $770.60 or $10,788.40 (dose intensity), based on a 70kg patient for each dose. 

Decreasing or stopping the production of alloantibodies requires therapies directed against mature plasma cells, memory B-cells or plasmablasts. Targeting memory B-cells or plasmablasts has a delayed onset of action as this therapy prevents new plasma cells from being formed but does not affect currently active ones. 

Rituximab 

A chimeric anti-CD20 monoclonal antibody, is dosed 375 mg/m2 or 1000 mg IV and given for one to two doses. The CD20 receptor is found on the surface of B-lymphocytes, including memory B-cells and immature plasmablasts, but not plasma cells. Rituximab has cytotoxic activity directly reducing B-lymphocyte and antibody levels. Cost for therapy ranges from $4,923.78 for dosing based on normal body surface area to $7,589.64 for a 1000mg dose. 

Bortezomib 

A proteasome inhibitor, is dosed 1.3 mg/m2 IV and given for four doses on days 1, 4, 8, and 11. Proteasome inhibition prevents protein biosynthesis resulting in apoptosis of the plasma cell and cessation of alloantibody production. Cost per dose based on a normal body surface area is $1,134.27. 

Eculizumab 

A humanized monoclonal antibody directed against C5, is dosed 600mg to 1200mg IV and administered weekly depending on alloantibody concentrations. Prevention of AMR is mediated by inhibition of membrane attack complex formation and halting activation of the complement cascade. Eculizumab is supplied as a 300mg vial for $6,638.40 or $13,276.80 to $26,553.60 per dose. 

Increasing the dose of maintenance immunosuppressive agents, including calcineurin inhibitors, antimetabolites, and steroids are also used to attenuate the immune system and help alleviate AMR. With all of the available treatment options, a multimodal approach is usually recommended to maximize chances of preventing graft injury. However, as you might see from the numbers above, careful clinical decision must be based on both efficacy and cost in order to responsibly avoid collapsing our already broken health care system. Instead of each center using its on protocol, our society should get together and perform a randomized trial with those interventions. Though I doubt this will happen any time soon, in particular with all the NIH budget cuts...

David Reardon, PharmD, PGY2 Critical Care Resident

Steve Gabardi, PharmD

Leonardo V Riella MD PhD (editing role)

Bortezomib in Myeloma Cast Nephropathy

Bortezomib is a proteosome inhibitor used primarily in the treatment of relapsed myeloma. However, it is increasingly being used in the management of myeloma cast nephropathy (MCN).

Bortezomib binds to, and inhibits the function of, the 26S proteosome in plasma cells. This proteosome ordinarily performs a housekeeping function, degrading ubiquitinylated proteins, and hence clearing the cell of abnormal or misfolded proteins. Inhibition prevents degradation of pro-apoptotic factors and results in programmed cell death. The secretory nature of myeloma cells makes them particularly susceptible to agents which interfere with the ubiquitin pathway. Bortezomib has additional effects on other intracellular signaling systems, such as the NF Kappa B pathway, which may attenuate proximal tubular damage from nephrotoxic monoclonal light chains.

There are now several small case series suggesting bortezomib is efficacious in MCN. One of these reports on 20 patients with relapsed MM and creatinine > 2mg/dL. Renal failure was reversed in 40% in under 3 weeks. Additionally, 50% of patients had a 50% improvement in serum creatinine over the course of one month. Toxicity did not appear to be increased.

Bortezomib is given intravenously and does not require dose reduction in renal impairment. For these reasons, bortezomib is likely to have a particularly important role in the future management of patients with monoclonal Ig-mediated kidney disease.

(Image taken from NEJM June 26 2003 Volume 348; 2597-2598)