Bispecifics Flashcards

1
Q

Define Bivalent?

A

has Fab region that recognises target protein sequence on both of its arms

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2
Q

How are diabodies different?

A

2 scFvs - designed to recognize different epitope - bispecific

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3
Q

Why are bispecifics complicated to make?

A

Heavy chains pair irrespective of what Fab is binding

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4
Q

What was the first bispecific?

A

Catumaxomab - mouse & rat chimera

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5
Q

What 2 antibodies make up Catumaxomab?

A

anti-EpCam Ab
anti-CD3 Ab

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6
Q

Why was catumaxomab ambitious?

A

targeting cancer & T cell - recruiting T cell to kill tumour cell

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7
Q

What was catumaxomab approved for treatment of?

A

Malignant ascites in Pts with EpCam-positive carcinoma

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8
Q

Why is Catumaxomab considered a trifunctional molecule?

A

Targets CD3 & EpCam to facilitate killing of tumour cells & Fc region creates a third functional binding site to facilitate ADCC

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9
Q

Why is the ADCC binding not optimised?

A

Fc region is not human

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10
Q

What does Catumaxomab consist of?

A

2 heavy chains
2 light chains
one each from 2 different antibodies

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11
Q

What are BiTEs?

A

Engineered by combining 2 scFc domains from 2 different Abs on one polypeptide chains

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12
Q

What connects the 2 scFv domains?

A

short flexible glycine-serine linker - faciliates bending

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13
Q

How big are BiTE?

A

55 kDa from CHO (non-glycosylated)

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14
Q

What is a problem with BiTEs?

A

No Fc portion - short half-life

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15
Q

What do BiTEs bridge?

A

target tumour cells to any T cells that naturally monitot their surroundings for pMHC ligand

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16
Q

What do 10-15 of these interactions of BiTEs lead to?

A

Formation of a cytolytic synapse similar to a pMHC-TCR interaction based immunologic synapse between APC & T cell

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17
Q

What is CD19?

A

PAN B cell marker - surface protein - bone marrow & circulatory system eg leukemia

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18
Q

Upon T cell binding what 5 thimgs are activated?

A

Upregulation of Cd25 & CD69
Secretion of cytokines
Proliferation
Production of granzyme & perforin

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19
Q

What is initiated in the cancer cell uponj binding?

A

Caspase pathway triggering of apoptosis

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20
Q

Why is it okay to use the murine blinatumomab?

A

Very high affinity binding to target & T cell receptor - targeting B cells - wiping out ab producing cells
- not going to target anti drug antibodies

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21
Q

What does Blinatumomab treat?

A

Pts with Philadelphia chromosome negative precrursor B-cell acute lymphoblastic leukemia

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22
Q

What did FDA grant Blincyto?

A

Breakthrough therapy designation
Priority review
Orphan product designation

23
Q

What does a rare disease mean?

A

Orphan disease - so few patients (1,440 pts in USA)

24
Q

What did a clinical trial for Blincyto show?

A

32% of participants had no evidence of disease (complete remission) for approx 6.7mths

25
What is B-ALL?
malignant neoplasm of B-lymphocyte progenitor cells or lymphoblasts
26
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
27
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
28
What are 4 charcateristics of Blinatumomab?
Cell-dependent T-cell activation cytokine release proliferation redirected serial lysis
29
What is Blinatumomab's half life?
2-3hr
30
How is blinatumomab adminstered?
continuous IV infusion 4 week period followed by a 2 week break to avoid T cell exhaustion
31
What is blinatumomab PD marked by?
Rapid, complete & sustained B-cell depletion
32
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
33
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
34
Which was better blinatumomab or chemo?
Significantly overall survival than chemo among Pts with relapsed or refractory B-cell precursor ALL
35
What is hemophilia A?
coagulation FVIII deficiency
36
What happens in 30% of Pts treated with exogenous FVIII?
Foreigness of FVIII molecule causes them to develop inhibitory Abs against FVIII
37
What does the poor pharmacokinetics of FVIII cause?
Low SC bioavailability & short half-life of 0.5d -> need frequent IV injectiosn
38
What was generated to overcome FVIII challenges?
Humanized bispecfic antibody to FIXa & FX called hBS23
39
What does hBS23 do?
Places 2 factors into spatially appropriate positions & mimica cofactor function of FVIII
40
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
41
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
42
What is Amivantamab?
Potent novel EGFR/c-MET bispecific antibody therapy for EGFR-mutated non-small cell lung cancer
43
What are majority of EGFR driver mutations in NSCLC sensitive to?
targeted tyrosine kinase inhibitors
44
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
45
Are there approved targeted therapy options for EGFR exon 20 insertions?
No & poor overall prognosis
46
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
47
What does Amivantamab do?
Fc-indepedent downmodulation of oncogenic signalling through heterodimerization & internalization of EGFR & c-MET receptors
48
What is the median duration of response for Amivantab?
11.1 mths
49
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
50
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
51
What other type of drug can bispecifics be used in?
Antibody drug conjugates eg. AZD9592
52
What does tetravalent molecule allow for?
Recognizes another epitope in HER2 - locks Ab on target
53
What does tetravalent molecules improve?
Promotes receptor clustering Faster internalization enhanced potency Low dosing = less adverse effects