Bispecifics Flashcards
Define Bivalent?
has Fab region that recognises target protein sequence on both of its arms
How are diabodies different?
2 scFvs - designed to recognize different epitope - bispecific
Why are bispecifics complicated to make?
Heavy chains pair irrespective of what Fab is binding
What was the first bispecific?
Catumaxomab - mouse & rat chimera
What 2 antibodies make up Catumaxomab?
anti-EpCam Ab
anti-CD3 Ab
Why was catumaxomab ambitious?
targeting cancer & T cell - recruiting T cell to kill tumour cell
What was catumaxomab approved for treatment of?
Malignant ascites in Pts with EpCam-positive carcinoma
Why is Catumaxomab considered a trifunctional molecule?
Targets CD3 & EpCam to facilitate killing of tumour cells & Fc region creates a third functional binding site to facilitate ADCC
Why is the ADCC binding not optimised?
Fc region is not human
What does Catumaxomab consist of?
2 heavy chains
2 light chains
one each from 2 different antibodies
What are BiTEs?
Engineered by combining 2 scFc domains from 2 different Abs on one polypeptide chains
What connects the 2 scFv domains?
short flexible glycine-serine linker - faciliates bending
How big are BiTE?
55 kDa from CHO (non-glycosylated)
What is a problem with BiTEs?
No Fc portion - short half-life
What do BiTEs bridge?
target tumour cells to any T cells that naturally monitot their surroundings for pMHC ligand
What do 10-15 of these interactions of BiTEs lead to?
Formation of a cytolytic synapse similar to a pMHC-TCR interaction based immunologic synapse between APC & T cell
What is CD19?
PAN B cell marker - surface protein - bone marrow & circulatory system eg leukemia
Upon T cell binding what 5 thimgs are activated?
Upregulation of Cd25 & CD69
Secretion of cytokines
Proliferation
Production of granzyme & perforin
What is initiated in the cancer cell uponj binding?
Caspase pathway triggering of apoptosis
Why is it okay to use the murine blinatumomab?
Very high affinity binding to target & T cell receptor - targeting B cells - wiping out ab producing cells
- not going to target anti drug antibodies
What does Blinatumomab treat?
Pts with Philadelphia chromosome negative precrursor B-cell acute lymphoblastic leukemia
What did FDA grant Blincyto?
Breakthrough therapy designation
Priority review
Orphan product designation
What does a rare disease mean?
Orphan disease - so few patients (1,440 pts in USA)
What did a clinical trial for Blincyto show?
32% of participants had no evidence of disease (complete remission) for approx 6.7mths
What is B-ALL?
malignant neoplasm of B-lymphocyte progenitor cells or lymphoblasts
What is Blinatumomab?
murine with dual specificities for human pan-B-cell antigen CD19 (10^-9) & CD3e chain of TCR complex (10^-7) with nanomolar bidning affinities
Which arm does blinatumomab bind first?
Binds tumour first - polarity
Want molecule to bind to target first - once bound free to engage T cell - do not want to elicit immune response first
What are 4 charcateristics of Blinatumomab?
Cell-dependent T-cell activation
cytokine release
proliferation
redirected serial lysis
What is Blinatumomab’s half life?
2-3hr
How is blinatumomab adminstered?
continuous IV infusion
4 week period followed by a 2 week break to avoid T cell exhaustion
What is blinatumomab PD marked by?
Rapid, complete & sustained B-cell depletion
What happened to b cell and T cell levels in blinatumomab?
No b-cell reconstitution was detectable throughout treatment
Ig recovery may take up to a year
Peripheral T cells exhibit redistribution pattern during 1st week & followed by an expansion & subsequent contraction phase in wks 2-4
What are increased T-cell counts due to after blinatumoab treatment?
Proliferation of memory T-cell subsets (CD8+ TEM & TERMA and/or CD4+ TEM & TCM
Which was better blinatumomab or chemo?
Significantly overall survival than chemo among Pts with relapsed or refractory B-cell precursor ALL
What is hemophilia A?
coagulation FVIII deficiency
What happens in 30% of Pts treated with exogenous FVIII?
Foreigness of FVIII molecule causes them to develop inhibitory Abs against FVIII
What does the poor pharmacokinetics of FVIII cause?
Low SC bioavailability & short half-life of 0.5d -> need frequent IV injectiosn
What was generated to overcome FVIII challenges?
Humanized bispecfic antibody to FIXa & FX called hBS23
What does hBS23 do?
Places 2 factors into spatially appropriate positions & mimica cofactor function of FVIII
What is FVIII action?
circulates in a complex with vWF
Activated by thrombin –> interacts with FIXa –> activates FX with FVa –> more thrombin activated –> cleaves fibrinogen into fibrin –> polymerizes crosslink using FXIII into a clot
What was the results of the trial with Emicizumab?
Significantly lower rate of bleeding events than no prophylaxis among particpants with hemophilia A with inhibitors
What is Amivantamab?
Potent novel EGFR/c-MET bispecific antibody therapy for EGFR-mutated non-small cell lung cancer
What are majority of EGFR driver mutations in NSCLC sensitive to?
targeted tyrosine kinase inhibitors
What are anti EGFRs TKIs susceptible to?
Resistance mechanisms through secondary mutations & lack efficacy against tumours with non-classical EGFR mutations like exon 20 insertions
Are there approved targeted therapy options for EGFR exon 20 insertions?
No & poor overall prognosis
Are there approved targeted therapies for NSCLC with EGFR mutations that are sensitive to TKIs?
No following progression on 3rd generation TKI without an alternative actionable mutation
What does Amivantamab do?
Fc-indepedent downmodulation of oncogenic signalling through heterodimerization & internalization of EGFR & c-MET receptors
What is the median duration of response for Amivantab?
11.1 mths
What were the results of Amivantamb in EGFR exon 20 insertion-mutated NSCLC CHRYSALIS trial?
Yielded robust & durable responses with tolerable safety patients with EGFR exon20ins mutations after progression on platinum-based chemo
What was the results of Amivantamab with chemo PAPILLON trial?
Superior efficacy as compared with chemo alone as 1st line treatment of pts with advanced NSCLC with EGFR exon 12 ins
What other type of drug can bispecifics be used in?
Antibody drug conjugates eg. AZD9592
What does tetravalent molecule allow for?
Recognizes another epitope in HER2 - locks Ab on target
What does tetravalent molecules improve?
Promotes receptor clustering
Faster internalization enhanced potency
Low dosing = less adverse effects
