Clinical pharmacology of vc-MMAE antibody–drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies

Figures & data

Table 1. ADCs, targets, and tumor indications of eight vc-MMAE ADCs included in the analysis

ADC Notation	ADC Names	Target	Circulating antigen	Studies (ClinicalTrials.gov number)	Tumor indications	Number of patients with PK data	Number of patients at 2.4 mg/kg	Dose and regimen (IV)	Ref.
ADC1	Pinatuzumab vedotin	CD22	No	DCT4862 (NCT01209130)	NHL	95	39	q3w: 0.1, 0.25, 0.5, 1.0, 1.8, 2.4, 3.2 mg/kg	^Citation11
ADC2	Polatuzumab vedotin	CD79b	No	DCS4968G (NCT01290549)	NHL	91	45	q3w: 0.1, 0.25, 0.5, 1.0, 1.8, 2.4 mg/kg	^Citation12
ADC3	DEDN6526A	ETBR	No	GO27935 (NCT01522664)	Melanoma	52	32	q3w: 0.3, 0.6, 1.2, 1.8, 2.4, 2.8 mg/kg	^Citation13
ADC4	DMOT4039A	MsLN	Yes	DMO4993G (NCT01469793)	Ovarian, Pancreatic	70	36	q3w: 0.2, 0.4, 0.8, 1.6, 2.4, 2.8 mg/kg; qw: 0.8, 1.0 and 1.2 mg/kg	^Citation14
ADC5	DMUC5754A	MUC16	Yes	DGR4980G (NCT01335958)	Ovarian, Pancreatic	54	39	q3w: 0.3, 0.6, 1.2, 1.8, 2.4, 3.2 mg/kg; qw: 0.8, 1.1, 1.4, 1.6 mg/kg	^Citation15
ADC6	DNIB0600A	Napi2b	No	DNB4987G (NCT01363947)	Ovarian, Lung	87	52	q3w: 0.2, 0.4, 0.7, 1.2, 1.8, 2.4, 2.8 mg/kg	^Citation16
ADC7	DSTP3086S	Steap1	No	DST4964G (NCT01283373)	Prostate	82	38	q3w: 0.3, 0.45, 0.67, 1.0, 1.5, 2.25, 2.4, 2.8 mg/kg;qw: 0.8, 1.0 mg/kg	^Citation17
ADC8	DFRF4539A	FcRH5	Yes	FRF4993g (NCT01432353)	Multiple Myeloma	33	17	q3w: 0.3, 0.6, 1.2, 1.8, 2.4 mg/kg; qw: 0.8; 1.1 mg/kg	^Citation18

ADCS: antibody–drug conjugates; PK: pharmacokinetics; q3w: once every 3 weeks; qw: once every week; NHL: non-Hodgkin lymphoma; IV: intravenous.

Table 2. PK parameters (mean ± SD [%CV]) of acMMAE, total antibody and unconjugated MMAE post the first dose of vc-MMAE ADCs at 2.4 mg/kg (90 min IV infusion)

ADC Notation	ADC Names	N	Cmax (ng/mL)	AUCinf (d*ng/mL)	CL (mL/d/kg)	Vdss (mL/kg)	t1/2 (d)
(a) acMMAE analyte
ADC1	Pinatuzumab vedotin	39	878 ± 240 [27.4]	2340 ± 805 [34.4]	21.8 ± 13.3 [61.1]	103 ± 33.1 [32.3]	6.18 ± 2.69 [43.5]
ADC2	Polatuzumab vedotin	45	887 ± 230 [25.9]	2610 ± 860 [33.0]	19.4 ± 10.9 [56.2]	91.7 ± 30.3 [33.0]	5.85 ± 2.46 [42.1]
ADC3	DEDN6526A	31	904 ± 191 [21.2]	2080 ± 743 [35.8]	22.6 ± 7.24 [32.0]	60.1 ± 19.9 [33.0]	4.62 ± 1.78 [38.5]
ADC4	DMOT4039A	36	725 ± 178 [24.5]	1440 ± 332 [23.1]	30.2 ± 7.36 [24.4]	96.0 ± 29.3 [30.5]	3.80 ± 1.15 [30.4]
ADC5	DMUC5754A	39	828 ± 201 [24.3]	1800 ± 501 [27.8]	25.6 ± 7.69 [30.0]	85.3 ± 24.7 [28.9]	5.12 ± 1.56 [30.5]
ADC6	DNIB0600A	51	923 ± 187 [20.3]	2300 ± 541 [23.5]	19.4 ± 4.71 [24.3]	92.3 ± 30.7 [33.2]	5.45 ± 1.50 [27.4]
ADC7	DSTP3086S	37	884 ± 172 [19.5]	2430 ± 489 [20.1]	17.4 ± 3.95 [22.7]	75.4 ± 21.5 [28.5]	5.84 ± 2.24 [38.4]
ADC8	DFRF4539A	16	885 ± 213 [24.1]	2710 ± 872 [32.2]	16.6 ± 7.69 [46.5]	77.4 ± 41.2 [53.2]	4.88 ± 2.48 [50.9]
ADC Notation	ADC Names	N	Cmax (µg/mL)	AUCinf (d*µg/mL)	CL (mL/d/kg)	Vdss (mL/kg)	t1/2 (d)
(b) total antibody
ADC1	Pinatuzumab vedotin	38	42.3 ± 13.1 [30.9]	255 ± 105 [41.1]	13.7 ± 14.5 [106]	128 ± 40.5 [31.5]	10.7 ± 6.00 [56.1]
ADC2	Polatuzumab vedotin	45	37.6 ± 11.0 [29.2]	208 ± 95.6 [45.9]	17.1 ± 16.5 [96.8]	110 ± 34.5 [31.4]	7.26 ± 3.75 [51.6]
ADC3	DEDN6526A	31	45.4 ± 10.9 [24.1]	128 ± 44.7 [35.0]	20.9 ± 7.18 [34.3]	70.6 ± 25.2 [35.7]	3.92 ± 1.68 [42.8]
ADC4	DMOT4039A	36	37.3 ± 9.21 [24.7]	120 ± 40.6 [34.0]	23.6 ± 13.8 [58.3]	118 ± 124 [106]	4.26 ± 1.45 [34.0]
ADC5	DMUC5754A	39	41.3 ± 8.15 [19.7]	175 ± 61.1 [34.9]	15.6 ± 6.47 [41.4]	93.1 ± 28.5 [30.6]	6.33 ± 2.85 [45.0]
ADC6	DNIB0600A	52	49.3 ± 10.4 [21.1]	200 ± 50.9 [25.4]	12.7 ± 3.24 [25.5]	98.1 ± 42.0 [42.8]	6.55 ± 2.76 [42.1]
ADC7	DSTP3086S	37	56.1 ± 13.6 [24.2]	315 ± 80.7 [25.6]	8.24 ± 2.66 [32.3]	63.2 ± 19.7 [31.2]	7.52 ± 3.18 [42.3]
ADC8	DFRF4539A	16	55.9 ± 17.3 [30.9]	301 ± 107 [35.6]	9.02 ± 4.73 [52.4]	61.5 ± 32.8 [53.3]	6.00 ± 2.98 [49.9]
ADC Notation	ADC Names	N	Cmax (ng/mL)	Tmax (d)* Median(range)	AUCinf (d*ng/mL)	t1/2 (d)
(c) Unconjugated MMAE
ADC1	Pinatuzumab vedotin	39	6.47 ± 4.81 [74.3]	3.09 (0.0660, 6.96)	51.2 ± 32.4 [63.3]	3.64 ± 0.879 [24.1]
ADC2	Polatuzumab vedotin	44	6.66 ± 4.63 [69.6]	2.95 (0.198, 9.75)	53.6 ± 28.0 [52.3]	3.75 ± 0.973 [26.0]
ADC3	DEDN6526A	32	6.72 ± 4.26 [63.4]	2.07 (1.03, 7.21)	50.3 ± 26.1 [51.7]	2.99 ± 0.648 [21.7]
ADC4	DMOT4039A	36	4.43 ± 2.52 [57.0]	2.03 (1.04, 7.01)	33.7 ± 17.8 [52.7]	3.35 ± 0.673 [20.1]
ADC5	DMUC5754A	39	7.01 ± 4.41 [63.0]	2.96 (1.07, 8.20)	57.6 ± 44.6 [77.4]	3.76 ± 1.57 [41.8]
ADC6	DNIB0600A	52	5.14 ± 3.26 [63.5]	2.06 (0.899, 7.22)	47.9 ± 32.4 [67.7]	4.15 ± 1.83 [44.1]
ADC7	DSTP3086S	36	5.71 ± 3.24 [56.7]	2.99 (1.98, 4.19)	43.3 ± 21.7 [50.0]	3.91 ± 0.654 [16.7]
ADC8	DFRF4539A	16	3.15 ± 1.51 [47.7]	3.10 (2.79, 7.27)	35.3 ± 18.4 [52.1]	5.00 ± 1.98 [39.6]

AUC_inf: area under the concentration–time curve from time zero to infinity; CL: clearance; C_max: maximum concentration; V_dss: volume of distribution at steady state; t_1/2: terminal half-life; T_max: time to C_max; CV: coefficient of variation; SD: standard deviation.

Figure 1. Chemical structure of a vc-MMAE ADC

Figure 2. Concentration (in nM)–time profiles (mean + SD) of acMMAE, total antibody and unconjugated MMAE (uMMAE) post the first dose of vc-MMAE ADCs at 2.4 mg/kg (90 min intravenous infusion)

acMMAE: antibody-conjugated MMAE, uMMAE: unconjugated MMAE; SD: standard deviation; ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC4 = DMOT4309A (MsLN); ADC5 = DMUC5754A (MUC-16); ADC6 = DNIB0600A (Napi2b); ADC7 = DSTP3086S (Steap1); ADC8 = DFRF4539A (FcRH5).

Figure 3. Exposure comparison of acMMAE, total antibody and unconjugated MMAE across the eight vc-MMAE ADCs post the first dose of vc-MMAE ADCs at 2.4 mg/kg (90 min intravenous infusion)

Open cycle: observed exposure for each patient, – : mean of exposure, acMMAE: antibody-conjugated MMAE, C_max: maximum concentration, AUC_inf: area under the concentration–time curve from time zero to infinity; ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC4 = DMOT4309A (MsLN); ADC5 = DMUC5754A (MUC-16); ADC6 = DNIB0600A (Napi2b); ADC7 = DSTP3086S (Steap1); ADC8 = DFRF4539A (FcRH5).

Figure 4. Dose-dependency of acMMAE and unconjugated MMAE PK for the eight vc-MMAE ADCs.

B. Dose-normalized AUC_inf at Cycle 1 of unconjugated MMAE vs dose

Open cycle: observed data, AUC_inf: area under the concentration–time curve from time zero to infinity, acMMAE: antibody-conjugated MMAE, ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC4 = DMOT4309A (MsLN); ADC5 = DMUC5754A (MUC-16); ADC6 = DNIB0600A (Napi2b); ADC7 = DSTP3086S (Steap1); ADC8 = DFRF4539A (FcRH5)

A. acMMAE clearance vs dose

Figure 5. Correlation of AUC_inf at Cycle 1 between analytes post the first dose of vc-MMAE ADCs over the doses tested (90 min IV infusion).

B. acMMAE vs unconjugated MMAE

Open cycle: observed data, The black line and shaded gray area represent linear regression model prediction and 90% confidence interval of predictions, acMMAE: antibody-conjugated MMAE, AUC_inf: area under the concentration–time curve from time zero to infinity, ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC4 = DMOT4309A (MsLN); ADC5 = DMUC5754A (MUC-16); ADC6 = DNIB0600A (Napi2b); ADC7 = DSTP3086S (Steap1); ADC8 = DFRF4539A (FcRH5)

A. acMMAE vs total antibody

Figure 6. Logistic regression analysis of exposure-efficacy (ORR) response relationship by acMMAE AUC_inf at Cycle 1

The black line and shaded gray area represent logistic regression model prediction and 90% confidence interval of predictions, open circle show exposure of individual patients with event (p = 1) and without events (p = 0), black solid circle and vertical lines show observed fraction of subjects with events in each exposure quartile and 90% confidence interval for these fractions. acMMAE: antibody-conjugated MMAE, AUC_inf: area under the concentration–time curve from time zero to infinity, ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC6 = DNIB0600A (Napi2b); iNHL = indolent non-Hodgkin’s Lymphomas; DLBCL = diffuse large B-cell lymphoma.

Figure 7. Logistic regression analysis of exposure-safety (Grade 2+ peripheral neuropathy) response relationship by acMMAE AUC_inf at Cycle 1

The black line and shaded gray area represent logistic regression model prediction and 90% confidence interval of predictions, open circle show exposure of individual patients with event (p = 1) and without events (p = 0), black solid circle and vertical lines show observed fraction of subjects with events in each exposure quartile and 90% confidence interval for these fractions. acMMAE: antibody-conjugated MMAE, AUC_inf: area under the concentration–time curve from time zero to infinity, ADC1 = Pinatuzumab vedotin (CD22); ADC2 = Polatuzumab vedotin (CD79b); ADC3 = DEDN6526A (ETBR); ADC6 = DNIB0600A (Napi2b).

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