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Biotherapeutics > Bispecifics > Flashcards

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
Q

What is B-ALL?

A

malignant neoplasm of B-lymphocyte progenitor cells or lymphoblasts

26
Q

What is Blinatumomab?

A

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
Q

Which arm does blinatumomab bind first?

A

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
Q

What are 4 charcateristics of Blinatumomab?

A

Cell-dependent T-cell activation
cytokine release
proliferation
redirected serial lysis

29
Q

What is Blinatumomab’s half life?

A

2-3hr

30
Q

How is blinatumomab adminstered?

A

continuous IV infusion
4 week period followed by a 2 week break to avoid T cell exhaustion

31
Q

What is blinatumomab PD marked by?

A

Rapid, complete & sustained B-cell depletion

32
Q

What happened to b cell and T cell levels in blinatumomab?

A

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
Q

What are increased T-cell counts due to after blinatumoab treatment?

A

Proliferation of memory T-cell subsets (CD8+ TEM & TERMA and/or CD4+ TEM & TCM

34
Q

Which was better blinatumomab or chemo?

A

Significantly overall survival than chemo among Pts with relapsed or refractory B-cell precursor ALL

35
Q

What is hemophilia A?

A

coagulation FVIII deficiency

36
Q

What happens in 30% of Pts treated with exogenous FVIII?

A

Foreigness of FVIII molecule causes them to develop inhibitory Abs against FVIII

37
Q

What does the poor pharmacokinetics of FVIII cause?

A

Low SC bioavailability & short half-life of 0.5d -> need frequent IV injectiosn

38
Q

What was generated to overcome FVIII challenges?

A

Humanized bispecfic antibody to FIXa & FX called hBS23

39
Q

What does hBS23 do?

A

Places 2 factors into spatially appropriate positions & mimica cofactor function of FVIII

40
Q

What is FVIII action?

A

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
Q

What was the results of the trial with Emicizumab?

A

Significantly lower rate of bleeding events than no prophylaxis among particpants with hemophilia A with inhibitors

42
Q

What is Amivantamab?

A

Potent novel EGFR/c-MET bispecific antibody therapy for EGFR-mutated non-small cell lung cancer

43
Q

What are majority of EGFR driver mutations in NSCLC sensitive to?

A

targeted tyrosine kinase inhibitors

44
Q

What are anti EGFRs TKIs susceptible to?

A

Resistance mechanisms through secondary mutations & lack efficacy against tumours with non-classical EGFR mutations like exon 20 insertions

45
Q

Are there approved targeted therapy options for EGFR exon 20 insertions?

A

No & poor overall prognosis

46
Q

Are there approved targeted therapies for NSCLC with EGFR mutations that are sensitive to TKIs?

A

No following progression on 3rd generation TKI without an alternative actionable mutation

47
Q

What does Amivantamab do?

A

Fc-indepedent downmodulation of oncogenic signalling through heterodimerization & internalization of EGFR & c-MET receptors

48
Q

What is the median duration of response for Amivantab?

A

11.1 mths

49
Q

What were the results of Amivantamb in EGFR exon 20 insertion-mutated NSCLC CHRYSALIS trial?

A

Yielded robust & durable responses with tolerable safety patients with EGFR exon20ins mutations after progression on platinum-based chemo

50
Q

What was the results of Amivantamab with chemo PAPILLON trial?

A

Superior efficacy as compared with chemo alone as 1st line treatment of pts with advanced NSCLC with EGFR exon 12 ins

51
Q

What other type of drug can bispecifics be used in?

A

Antibody drug conjugates eg. AZD9592

52
Q

What does tetravalent molecule allow for?

A

Recognizes another epitope in HER2 - locks Ab on target

53
Q

What does tetravalent molecules improve?

A

Promotes receptor clustering
Faster internalization enhanced potency
Low dosing = less adverse effects

Biotherapeutics (9 decks)

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